ORESTES VICENTE FORLENZA

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Departamento de Psiquiatria, Faculdade de Medicina - Docente
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina

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  • article 67 Citação(ões) na Scopus
    White matter abnormalities associated with Alzheimer's disease and mild cognitive impairment: a critical review of MRI studies
    (2013) RADANOVIC, Marcia; PEREIRA, Fabricio Ramos Silvestre; STELLA, Florindo; APRAHAMIAN, Ivan; FERREIRA, Luiz Kobuti; FORLENZA, Orestes Vicente; BUSATTO, Geraldo F.
    In this article, the authors aim to present a critical review of recent MRI studies addressing white matter (WM) abnormalities in Alzheimer's disease (AD) and mild cognitive impairment (MCI), by searching PubMed and reviewing MRI studies evaluating subjects with AD or MCI using WM volumetric methods, diffusion tensor imaging and assessment of WM hyperintensities. Studies have found that, compared with healthy controls, AD and MCI samples display WM volumetric reductions and diffusion tensor imaging findings suggestive of reduced WM integrity. These changes affect complex networks relevant to episodic memory and other cognitive processes, including fiber connections that directly link medial temporal structures and the corpus callosum. Abnormalities in cortico-cortical and cortico-subcortical WM interconnections are associated with an increased risk of progression from MCI to dementia. It can be concluded that WM abnormalities are detectable in early stages of AD and MCI. Degeneration of WM networks causes disconnection among neural cells and the degree of such changes is related to cognitive decline.
  • article 51 Citação(ões) na Scopus
    Neuropsychiatric symptoms in the prodromal stages of dementia
    (2014) STELLA, Florindo; RADANOVIC, Marcia; BALTHAZAR, Marcio L. F.; CANINEU, Paulo R.; SOUZA, Leonardo C. de; FORLENZA, Orestes V.
    Purpose of reviewTo critically discuss the neuropsychiatric symptoms in the prodromal stages of dementia in order to improve the early clinical diagnosis of cognitive and functional deterioration.Recent findingsCurrent criteria for cognitive syndrome, including Alzheimer's disease, comprise the neuropsychiatric symptoms in addition to cognitive and functional decline. Although there is growing evidence that neuropsychiatric symptoms may precede the prodromal stages of dementia, these manifestations have received less attention than traditional clinical hallmarks such as cognitive and functional deterioration. Depression, anxiety, apathy, irritability, agitation, sleep disorders, among other symptoms, have been hypothesized to represent a prodromal stage of dementia or, at least, they increase the risk for conversion from minor neurocognitive disorder to major neurocognitive disorder. Longitudinal investigations have provided increased evidence of progression to dementia in individuals with minor neurocognitive disorder when neuropsychiatric symptoms also were present.SummaryAlthough neuropsychiatric symptoms are strongly associated with a higher risk of cognitive and functional deterioration, frequently the clinician does not acknowledge these conditions as increasing the risk of dementia. When the clinician accurately diagnoses neuropsychiatric symptoms in the prodromal stage of dementia, he could early establish appropriate treatment and, may be, delay the beginning of clinical and functional deterioration.
  • article 70 Citação(ões) na Scopus
    Lithium and neuroprotection: translational evidence and implications for the treatment of neuropsychiatric disorders
    (2013) DINIZ, Breno Satler; MACHADO-VIEIRA, Rodrigo; FORLENZA, Orestes Vicente
    In the last two decades, a growing body of evidence has shown that lithium has several neuroprotective effects. Several neurobiological mechanisms have been proposed to underlie these clinical effects. Evidence from preclinical studies suggests that neuroprotection induced by lithium is mainly related to its potent inhibition of the enzyme glycogen synthase kinase-3 beta (GSK-3 beta) and its downstream effects, ie, reduction of both tau protein phosphorylation and amyloid-beta(42) production. Additional neuroprotective effects include increased neurotrophic support, reduced proinflammatory status, and decreased oxidative stress. More recently, neuroimaging studies in humans have demonstrated that chronic use is associated with cortical thickening, higher volume of the hippocampus and amygdala, and neuronal viability in bipolar patients on lithium treatment. In line with this evidence, observational and case registry studies have shown that chronic lithium intake is associated with a reduced risk of Alzheimer's disease in subjects with bipolar disorder. Evidence from recent clinical trials in patients with mild cognitive impairment suggests that chronic lithium treatment at subtherapeutic doses can reduce cerebral spinal fluid phosphorylated tau protein. Overall, convergent lines of evidence point to the potential of lithium as an agent with disease modifying properties in Alzheimer's disease. However, additional long-term studies are necessary to confirm its efficacy and safety for these patients, particularly as chronic intake is necessary to achieve the best therapeutic results.
  • article 171 Citação(ões) na Scopus
    Nonpharmacological Interventions to Reduce Behavioral and Psychological Symptoms of Dementia: A Systematic Review
    (2015) OLIVEIRA, Alexandra Martini de; RADANOVIC, Marcia; MELLO, Patricia Cotting Homem de; BUCHAIN, Patricia Cardoso; VIZZOTTO, Adriana Dias Barbosa; CELESTINO, Diego L.; STELLA, Florindo; PIERSOL, Catherine V.; FORLENZA, Orestes V.
    Introduction. Behavioral and psychological symptoms of dementia (BPSD) are defined as a group of symptoms of disturbed perceptive thought content, mood, or behavior that include agitation, depression, apathy, repetitive questioning, psychosis, aggression, sleep problems, and wandering. Care of patients with BPSD involves pharmacological and nonpharmacological interventions. We reviewed studies of nonpharmacological interventions published in the last 10 years. Methods. We performed a systematic review in Medline and Embase databases, in the last 10 years, until June 2015. Key words used were (1) nonpharmacological interventions, (2) behavioral symptoms, (3) psychological symptoms, and (4) dementia. Results. We included 20 studies published in this period. Among these studies, program activities were more frequent (five studies) and the symptoms more responsive to the interventions were agitation. Discussion. Studies are heterogeneous in many aspects, including size sample, intervention, and instruments of measures. Conclusion. Nonpharmacological interventions are able to provide positive results in reducing symptoms of BPSD. Most studies have shown that these interventions have important and significant efficacy.
  • article 16 Citação(ões) na Scopus
    Cognitive impairment and dementia in late-life bipolar disorder
    (2013) APRAHAMIAN, Ivan; NUNES, Paula V.; FORLENZA, Orestes V.
    Purpose of review This work aims to review the most recent publications on cognitive impairment and dementia associated with bipolar disorder (BPD), especially in the elderly. Recent findings In the last years, a growing number of studies aiming at better understanding of cognitive impairment in BPD were found. Impairments found in BPD were compared with other psychiatric disorders and primary cognitive diseases. The impact of cognitive impairment on functionality was also recently highlighted. With respect to neurobiology, studies that explored inflammatory, neurotrophic and pathological cascades possibly associated with BPD and cognition were published. Finally, the first study covering treatment of cognitive impairment was carried out with pramipexole, and it raised important methodological issues for future research in BPD. Summary Cognitive impairment and dementia in BPD should be better explored with cognitive and functionality protocols along with biological and neuroimaging markers.
  • article 6 Citação(ões) na Scopus
    Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: a systematic review
    (2021) STELLA, Florindo; VALIENGO, Leandro C. Lane; PAULA, Vanessa J. R. de; LIMA, Carlos Augusto de Mendonca; FORLENZA, Orestes V.
    Introduction: Neuropsychiatric symptoms are an integral component of the natural history of dementia, occurring from prodromal to advanced stages of the disease process and causing increased burden and morbidity. Clinical presentations are pleomorphic and clinical management often requires combinations of pharmacological and non-pharmacological interventions. However, limited efficacy and a non-negligible incidence of adverse psychotropic drug events emphasize the need for novel therapeutic options. Objectives: To review the evidence supporting use of medical cannabinoids for treatment of neuropsychiatric symptoms (NPS) of dementia. Methods: We conducted a systematic review of the medical literature to examine scientific publications reporting use of medical cannabinoids for treatment of NPS. Medical Subject Headings (MeSH) were used to search for relevant publications and only papers reporting original clinical information were included. A secondary search was performed within selected publications to capture relevant citations that were not retrieved by the systematic review. The papers selected were categorized according to the level of evidence generated by the studies in relation to this clinical application, i.e. (1) controlled clinical trials; (2) open-label or observational studies; and (3) case reports. Results: Fifteen publications with original clinical data were retrieved: five controlled clinical trials, three open-label/observational studies, and seven case reports. Most studies indicated that use of medical cannabinoids engendered favorable outcomes for treatment of NPS related to moderate and advanced stages of dementia, particularly agitation, aggressive behavior, sleep disorder, and sexual disinhibition. Conclusion: Medical cannabinoids constitute a promising pharmacological approach to treatment of NPS with preliminary evidence of benefit in at least moderate to severe dementia. Controlled trials with longitudinal designs and larger samples are required to examine the long-term efficacy of these drugs in different types and stages of dementia, in addition to their adverse events and risk of interactions with other drugs. Many pharmacological details are yet to be determined, such as dosing, treatment duration, and concentrations of active compounds (e.g., cannabidiol [CBD]/Delta(9)-tetrahydrocannabinol [THC] ratio) in commercial preparations of medical cannabinoids.
  • article 22 Citação(ões) na Scopus
    Recent advances in the management of neuropsychiatric symptoms in dementia
    (2017) FORLENZA, Orestes V.; LOUREIRO, Julia Cunha; PAIS, Marcos Vasconcelos; STELLA, Florindo
    Purpose of review The present article addresses intriguing questions related to the clinical intervention in distinct neuropsychiatric syndromes of patients with dementia. Recent findings We reviewed 154 articles published between 2015 and 2016 targeting psychopharmacological and nonpharmacological interventions, and safety-tolerability concerns. We selected 115 articles addressing the purpose of this study. Of these, 33 were chosen because they were dedicated to subtopics: agitation (42), depression (33), apathy (18), sleep disorders/anxiety (8), and psychosis (4). Clinical studies using both pharmacological (70) and nonpharmacological (37) interventions were considered; others were included for theoretical support. Regarding the methodological design, we found double-blind RCTs (17), single-blinded RCTs (4), open-label studies (18), case reports (5), cross-sectional or cohort studies (25), epidemiological papers (2), and expert reviews (44). This observation raises concerns about the overall methodological adequacy of a substantial proportion of studies in this field, which limits the potential of generalization of the findings. Finally, 18 studies were designed to determine safety-tolerability issues of psychotropic medications (6 were discussed). Summary Effective and well tolerated treatment of neuropsychiatric syndromes in dementia remains a critically unsolved challenge. We understand that this is an extremely important area of research, and critically required to guide clinical decisions in geriatric neuropsychiatry.
  • article 30 Citação(ões) na Scopus
    Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: A systematic review and meta-analysis
    (2019) VACAS, Sara M.; STELLA, Florindo; LOUREIRO, Julia C.; COUTO, Frederico Simoes do; OLIVEIRA-MAIA, Albino J.; FORLENZA, Orestes V.
    Background Pharmacological and conventional nonpharmacological treatments for behavioural and psychological symptoms of dementia (BPSD) have only modest efficacy. Furthermore, pharmacotherapy carries the risk of important side effects. Noninvasive brain stimulation (repetitive transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS)) are valuable and safe for cognitive function in Alzheimer disease (AD). However, there have been few studies, and there is no consensus, regarding the use of these techniques to treat BPSD. Methods We performed a systematic review of the literature and meta-analysis of studies reporting the effect of rTMS or tDCS on BPSD. Results Seven articles were included: five randomized, controlled clinical trials and two open-label clinical trials. Five studies investigated the effects of rTMS and two the effects of tDCS. Both studies using tDCS reported no evidence of efficacy on BPSD, while two of the three RCTs using rTMS found statistically significant benefits. In an exploratory meta-analysis with four of the RCT studies, we did not find evidence of efficacy of noninvasive brain stimulation techniques, with an overall effect of -0.02 (95% CI = -0.90, 0.94; I-2 = 85%). However, when we used only the data from the studies that applied rTMS, we found a positive effect on BPSD, with an overall effect of -0.58 (95% CI = -1.02, -0.14; I-2 = 0%). With regards to the adverse effects reported, these were mild and not clinically relevant. Conclusions Our results establish a tendency for efficacy of rTMS protocols on BPSD, while corroborating their safety and tolerability, suggesting the need for further research.
  • article 40 Citação(ões) na Scopus
    Passive antiamyloid immunotherapy for Alzheimer's disease
    (2020) LOUREIRO, Julia C.; PAIS, Marcos V.; STELLA, Florindo; RADANOVIC, Marcia; TEIXEIRA, Antonio Lucio; FORLENZA, Orestes V.; SOUZA, Leonardo Cruz de
    Purpose of review Antiamyloid therapy of Alzheimer's disease tackles the overproduction and clearance of the amyloid-beta peptide (A beta). Immunotherapeutic compounds were tested in large-scale trials. We revisit the recent literature focusing on randomized-controlled trials (RCT) using monoclonal anti-A beta antibodies. Recent findings Forty-three articles on anti-A beta passive immunotherapy for Alzheimer's disease were published between January 2016 and October 2019 regarding 17 RCTs: 13 phase III trials using the monoclonal antibodies bapineuzumab, solanezumab, gantenerumab, crenezumab, and aducanumab; three phase II with crenezumab and aducanumab; and one phase I trial with BAN2401. Studies resulted largely negative considering the effect of the treatment on primary and secondary outcome variables. The incidence of the most important adverse effect, amyloid-related imaging abnormalities (ARIAs) ranged between 0.2 and 22%, in treatment groups. Primary endpoints were not met in eight trials, and five trials were discontinued prior to completion. Passive immunotherapy RCTs failed to show clinically relevant effects in patients with clinically manifest or prodromal dementia. The high incidence of ARIAs indicates that the risk of adverse events may outweigh the benefits of these interventions. Ongoing studies must determine the benefit of such interventions in preclinical Alzheimer's disease, addressing the effect of antiamyloid immunotherapy in samples of asymptomatic carriers of autosomal-dominant mutations related to early-onset Alzheimer's disease.
  • article 36 Citação(ões) na Scopus
    Cognitive decline following acute viral infections: literature review and projections for post-COVID-19
    (2022) DAMIANO, Rodolfo Furlan; GUEDES, Bruno F.; ROCCA, Cristiana Castanho de; SERAFIM, Antonio de Padua; CASTRO, Luiz Henrique Martins; MUNHOZ, Carolina Demarchi; NITRINI, Ricardo; BUSATTO FILHO, Geraldo; MIGUEL, Euripedes Constantino; LUCCHETTI, Giancarlo; FORLENZA, Orestes
    Recently, much attention has been drawn to the importance of the impact of infectious disease on human cognition. Several theories have been proposed, to explain the cognitive decline following an infection as well as to understand better the pathogenesis of human dementia, especially Alzheimer's disease. This article aims to review the state of the art regarding the knowledge about the impact of acute viral infections on human cognition, laying a foundation to explore the possible cognitive decline followed coronavirus disease 2019 (COVID-19). To reach this goal, we conducted a narrative review systematizing six acute viral infections as well as the current knowledge about COVID-19 and its impact on human cognition. Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals, which could be accounted for by direct and indirect pathways to brain dysfunction. Understanding this scenario might help clinicians and health leaders to deal better with a wave of neuropsychiatric issues that may arise following COVID-19 pandemic as well as with other acute viral infections, to alleviate the cognitive sequelae of these infections around the world.