ORESTES VICENTE FORLENZA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Psiquiatria, Faculdade de Medicina - Docente
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
10 resultados
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- Heterogeneity of Cerebrospinal Fluid Biomarkers Profiles in Individuals with Distinct Levels of Cognitive Decline: A Cross-Sectional Study(2021) PAIS, Marcos; LOUREIRO, Julia; VALE, Vagner do; RADANOVIC, Marcia; TALIB, Leda; STELLA, Florindo; FORLENZA, OrestesBackground: Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-beta (A beta), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer's disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice. Objective: To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment. Methods: 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n = 60, 29.4%); MCI (n = 84, 41.2%); or normal cognition (NC, n = 60, 29.4%). CSF concentrations of A beta(42), T-tau, and (181)Thr-P-tau were determined, and A beta(42)/P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD. Results: The majority (73.7%) of patients in the AD group had the A beta(42)/P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A+, 28 (46.7%) as T+, and 23 (38.3%) as N+. In the AD group, 66.7% of the cases were classified as A+, 78.3% as T+, and 80% as N+. Conclusion: Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases.
- Diagnostic Performance of an Eye-Tracking Assisted Visual Inference Language Test in the Assessment of Cognitive Decline due to Alzheimer's Disease(2023) BELAN, Ariella Fornachari Ribeiro; PAIS, Marcos Vasconcelos; CAMARGO, Marina von Zuben de Arruda; ANA, Livea Carla Fidalgo Garcez Sant'; RADANOVIC, Marcia; FORLENZA, Orestes VicenteBackground: The assessment of language changes associated with visual search impairment can be an important diagnostic tool in the Alzheimer's disease (AD) continuum. Objective: Investigate the performance of an eye-tracking assisted visual inference language task in differentiating subjects with mild cognitive impairment (MCI) or AD dementia from cognitively unimpaired older adults (controls). Methods: We assessed a group of 95 older adults (49 MCI, 18 mild dementia due to AD, and 28 controls). The subjects performed the same task under multiple experimental conditions which generate correlated responses that need to be taken into account. Thus, we performed a non-parametric repeated measures ANOVA model for verbal answers, and a linear mixed model (LMM) or its generalized version for the analysis of eye tracking variables. Results: Significant differences were found in verbal answers across all diagnostic groups independently of type of inference, i.e., logic or pragmatic. Also, eye-tracking parameters were able to discriminate AD from MCI and controls. AD patients did more visits to challenge stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011), more visits to the correct response stimulus (Control-AD, -1.363, SE = 0.383, p = 0.002; MCI-AD, -0.946, SE = 0.349, p = 0.022), more fixations on distractors (Control-AD, -4.580, SE = 1.172, p = 0.001; MCI-AD, -2.940, SE = 1.070, p = 0.020), and a longer time to first fixation on the correct response stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011). Conclusion: The analysis of oculomotor behavior along with language assessment protocols may increase the sensitivity for detection of subtle deficits in the MCI-AD continuum, representing an important diagnostic tool.
- Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice(2018) CARDILLO, Giancarlo de Mattos; DE-PAULA, Vanessa de Jesus Rodrigues; IKENAGA, Eliza Hiromi; COSTA, Luciana Rodrigues; CATANOZI, Sergio; SCHAEFFER, Evelin Lisete; GATTAZ, Wagner Farid; KERR, Daniel Shikanai; FORLENZA, Orestes VicenteTelomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL.
- Decreased Neurotrophic Support is Associated with Cognitive Decline in Non-Demented Subjects(2015) FORLENZA, Orestes Vicente; MIRANDA, Aline Silva; BARBOSA, Izabela Guimaraes; TALIB, Leda Leme; DINIZ, Breno Satler; GATTAZ, Wagner Farid; TEIXEIRA, Antonio LucioBackground: There is evidence of decreased neurotrophic support in Alzheimer's disease (AD), including its prodromal stages, but it is not clear whether this abnormality represents a marker of this process. Objective: To determine serum concentrations of a panel of neurotrophic factors (BDNF, NGF, and GDNF) in a cross-section of elderly patients with mild cognitive impairment (MCI) and AD compared to cognitively healthy controls, and to evaluate whether abnormal levels of these factors at baseline predict the transition from MCI to dementia. Methods: A total of 134 older adults were enrolled in this study. Twenty-six patients with mild to moderate AD, 62 with MCI, and 46 cognitively healthy older adults (controls) were subjected to a clinical evaluation including several cognitive tests. Peripheral blood was drawn and serum levels of BDNF, NGF, and GDNF were measured by enzyme-linked immunosorbent assay. APOE genotyping was performed by PCR assays. Results: Serum concentrations of BDNF, NGF, and GDNF were significantly reduced in cognitively impaired subjects (i.e., MCI and AD) as compared to controls, although only the former two remained statistically different after controlling for age, gender, and cognitive performance (p = 0.05 and p = 0.01, respectively). Lower BDNF and NGF levels were also observed in the sub-sample of MCI patients who progressed to dementia upon follow-up (p = 0.02 and p = 0.002, respectively). Conclusion: Abnormalities in neurotrophic systems are observed at early stages of AD and may represent a marker of cognitive deterioration.
- Adjunctive Therapy to Manage Neuropsychiatric Symptoms in Moderate and Severe Dementia: Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program(2021) OLIVEIRA, Alexandra Martini; RADANOVIC, Marcia; MELLO, Patricia Cotting Homem de; BUCHAIN, Patricia Cardoso; VIZZOTTO, Adriana Dias Barbosa; HARDER, Janaina; STELLA, Florindo; GITLIN, Laura N.; PIERSOL, Catherine Verrier; VALIENGO, Leandro L. C.; FORLENZA, Orestes VicenteBackground: Neuropsychiatric symptoms (NPS) such as aggression, apathy, agitation, and wandering may occur in up to 90%of dementia cases. International guidelines have suggested that non-pharmacological interventions are as effective as pharmacological treatments, however without the side effects and risks of medications. An occupational therapy method, called Tailored Activity Program (TAP), was developed with the objective to treat NPS in the elderly with dementia and has been shown to be effective. Objective: Evaluate the efficacy of the TAP method (outpatient version) in the treatment of NPS in individuals with dementia and in the burden reduction of their caregivers. Methods: This is a randomized, double-blind, controlled clinical trial for the treatment of NPS in dementia. Outcome measures consisted of assessing the NPS of individuals with dementia, through the Neuropsychiatric Inventory-Clinician rating scale (NPI-C), and assessing the burden on their caregivers, using the Zarit Scale. All the participants were evaluated pre-and post-intervention. Results: 54 individuals with dementia and caregivers were allocated to the experimental (n = 28) and control (n = 26) groups. There was improvement of the following NPS in the experimental group: delusions, agitation, aggressiveness, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, and aberrant vocalization. No improvement was observed in hallucinations, sleep disturbances, and appetite disorders. The TAP method for outpatient settings was also clinically effective in reducing burden between caregivers of the experimental group. Conclusion: The use of personalized prescribed activities, coupled with the caregiver training, may be a clinically effective approach to reduce NPS and caregiver burden of individuals with dementia.
- Visual Search Efficiency in Mild Cognitive Impairment and Alzheimer's Disease: An Eye Movement Study(2020) PEREIRA, Marta Luisa Goncalves de Freitas; CAMARGO, Marina von Zuben de Arruda; BELLAN, Ariella Fornachari Ribeiro; TAHIRA, Ana Carolina; SANTOS, Bernardo dos; SANTOS, Jessica dos; MACHADO-LIMA, Ariane; NUNES, Fatima L. S.; FORLENZA, Orestes VicenteBackground: Visual search abilities are essential to everyday life activities and are known to be affected in Alzheimer's disease (AD). However, little is known about visual search efficiency in mild cognitive impairment (MCI), a transitive state between normal aging and dementia. Eye movement studies and machine learning methods have been recently used to detect oculomotor impairments in individuals with dementia. Objective: The aim of the present study is to investigate the association between eye movement metrics and visual search impairment in MCI and AD. Methods: 127 participants were tested: 43 healthy controls, 51 with MCI, and 33 with AD. They completed an eyetracking visual search task where they had to find a previously seen target stimulus among distractors. Results: Both patient groups made more fixations on the screen when searching for a target, with longer duration than controls. MCI and AD fixated the distractors more often and for a longer period of time than the target. Healthy controls were quicker and made less fixations when scanning the stimuli for the first time. Machine-learning methods were able to distinguish between controls and AD subjects and to identify MCI subjects with a similar oculomotor profile to AD with a good accuracy. Conclusion: Results showed that eye movement metrics are useful for identifying visual search impairments in MCI and AD, with possible implications in the early identification of individuals with high-risk of developing AD.
- Protein Expression of BACE1 is Downregulated by Donepezil in Alzheimer's Disease Platelets(2017) SARNO, Tamires Alves; TALIB, Leda Leme; JOAQUIM, Helena Passarelli Giroud; BRAM, Jessyka Maria de Franca; GATTAZ, Wagner Farid; FORLENZA, Orestes VicenteBackground: Abnormal amyloid-beta protein precursor (A beta PP) metabolism is a key feature of Alzheimer's disease (AD). Platelets contain most of the enzymatic machinery required for A beta PP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, A beta PP-related molecules in platelets may be regarded as peripheral markers of AD. Objective: We sought to determine the protein expression of the A beta PP secretases (ADAM10, BACE1, and PSEN1) and A beta PP ratio in platelets of patients with mild or moderate AD compared to healthy controls. We further determined whether the protein expression of these markers might be modified by chronic treatment with donepezil. Methods: Platelet samples were obtained from patients and controls at baseline and after 3 and 6 months of continuous treatment with therapeutic doses of donepezil. The protein expression of platelet markers was determined by western blotting. Results: AD patients had a significant decrease in A beta PP ratio, ADAM10, and PSEN1 compared to controls at baseline, but these differences were not modified by the treatment. Nonetheless, a significant reduction in the protein expression of BACE1 was observed in patients treated with donepezil for 6 months. Conclusion: Our results corroborate previous findings from our group and others of decreased A beta PP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification.
- Impact of Cognitive Demand on Eye Movement Pattern in Patients with Alzheimer's Disease(2022) CAMARGO, Marina von Zuben de Arruda; PAIS, Marcos Vasconcelos; BELLAN, Ariella Fornachari Ribeiro; TAHIRA, Ana Carolina; SANTOS, Bernardo dos; SANT'ANA, Livea Carla Fidalgo Garcez; RADANOVIC, Marcia; FORLENZA, Orestes VicenteBackground: Eye-movement behavior has been used as a reliable tool to identify cognitive and behavioral patterns in individuals with different neuropsychiatric disorders including Alzheimer's disease (AD). Most studies in the field have been dedicated to evaluating eye-movement behavior during cognitive tasks in different protocols using multiple parameters. Objective: We aimed to evaluate the differences of eye-movement behavior in healthy subjects, subjects with mild cognitive impairment (MCI), and those with AD in a simple color task with and without cognitive demand. Methods: 91 subjects: 18 AD, 47 MCI, and 26 healthy controls had their oculomotor parameters assessed during baseline (no cognitive demand involved) and during a simple computational color memory task using an eye-tracker. Results: Baseline showed statistically different and heterogeneous results between normal cognition and MCI groups. Familiarization phase of the task could not discriminate between groups in any of the analyzed parameters. AD subjects made longer fixations and visits on distractors, and more frequent fixations and visits on the target areas than other groups during the response phase. Conclusion: Eye-tracking time-related parameters differentiate AD subjects from other groups under cognitive demand even in a simple color memory task.
- Relationship Between PET-Assessed Amyloid Burden and Visual and Verbal Episodic Memory Performance in Elderly Subjects(2020) SQUARZONI, Paula; FARIA, Daniele de Paula; YASSUDA, Monica Sanches; PORTO, Fabio Henrique de Gobbi; COUTINHO, Artur Martins; COSTA, Naomi Antunes da; NITRINI, Ricardo; FORLENZA, Orestes Vicente; DURAN, Fabio Luiz de Souza; BRUCKI, Sonia Maria Dozzi; BUCHPIGUEL, Carlos Alberto; BUSATTO, Geraldo F.Background: Studies of elderly subjects using biomarkers that are proxies for Alzheimer's disease (AD) pathology have the potential to document meaningful relationships between cognitive performance and biomarker changes along the AD continuum. Objective: To document cognitive performance differences across distinct AD stages using a categorization based on the presence of PET-assessed amyloid-beta (A beta) burden and neurodegeneration. Methods: Patients with mild dementia compatible with AD (n = 38) or amnestic mild cognitive impairment (aMCI; n = 43) and a cognitively unimpaired group (n = 27) underwent PET with Pittsburgh compound-B (PiB) assessing A beta aggregation (A+) and [F-18]FDG-PET assessing neurodegeneration ((N)+). Cognitive performance was assessed with verbal and visual episodic memory tests and the Mini-Mental State Examination. Results: The A+(N)+ subgroup (n = 32) showed decreased (p < 0.001) cognitive test scores compared to both A+(N)-(n = 18) and A-(N)- (n = 49) subjects, who presented highly similar mean cognitive scores. Despite its modest size (n = 9), the A-(N)+ subgroup showed lower (p < 0.043) verbal memory scores relative to A-(N)- subjects, and trend lower (p = 0.096) scores relative to A+(N)- subjects. Continuous A beta measures (standard uptake value ratios of PiB uptake) were correlated most significantly with visual memory scores both in the overall sample and when analyses were restricted to dementia or (N)+ subjects, but not in non-dementia or (N)- groups. Conclusion: These results demonstrate that significant A beta-cognition relationships are highly salient at disease stages involving neurodegeneration. The fact that findings relating A beta burden to memory performance were detected only at (N)+ stages, together with the similarity of test scores between A+(N)- and A-(N)- subjects, reinforce the view that A beta-cognition relationships during early AD stages may remain undetectable unless substantially large samples are evaluated.
- Neurobiological Correlates of Apathy in Alzheimer's Disease and Mild Cognitive Impairment: A Critical Review(2014) STELLA, Florindo; RADANOVIC, Marcia; APRAHAMIAN, Ivan; CANINEU, Paulo Renato; ANDRADE, Larissa Pires de; FORLENZA, Orestes VicenteBackground: In Alzheimer's disease (AD) and mild cognitive impairment (MCI), apathy was associated with faster clinical deterioration. Studies involving neurobiological correlates such as neuroimaging and biomarkers have presented distinct results. Objective: This work aimed to analyze neurobiological correlates of apathy in AD and MCI based on evidence from the literature involving brain neuroimaging and classical AD biomarkers. Methods: This review comprised studies published from 1996 to June 2013 from the Pubmed database. The studies were divided into Part I (neuroimaging) and Part II (chemical biomarkers). The analysis included the identification of brain regions involved and assessments of apathy and cognition. We found 68 publications: 33 fulfilled the inclusion criteria; 35 were case reports or were not clear about the measurements of apathy and were excluded. From the 33 eligible studies, 26 were classified into part I, and 7 studies were included in part II. We created specific criteria to appropriately classify the quality level of each publication. Results: Prefrontal regions and the anterior cingulate were the leading brain areas associated with apathy in AD and MCI. Other regions, including cortical and subcortical structures, have also been implicated in this syndrome. Conclusions: Abnormalities in frontal regions (associated with impairments in planning and decision making) and anterior cingulate (related to emotional blunting and loss of motivation) were the crucial structures associated with apathy in AD and MCI.