The effect of diphenylethane side-chain substituents on dibenzocyclohexadiene formation and their inhibition of α-synuclein aggregation in vitro.

The naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular cyclization at pH 7.4 to form dibenzocyclooctadienes. Both NDGA and these dibenzocyclooctadienes have been shown to prevent in vitro aggregation of α-synuclein, an intrinsically disordered protein associated with Parkinson's disease. NDGA possesses two vicinal methyl groups on the butyl linker and the presence of these methyl groups attenuates the rate of intramolecular cyclization versus the unsubstituted analog, in opposition to the anticipated Thorpe-Ingold effect, likely due to steric repulsions during cyclization. Numerous 1,2-bis-ethane di-catechols are known to inhibit α-synuclein aggregation in vitro and we hypothesize that these compounds undergo a similar intramolecular cyclization and the cyclized products may be responsible for the activity. To test this hypothesis we prepared a series of 1,2-bis-ethane di-catechols with 0, 2 and 4 methyl substituents on the linker. We have confirmed that these compounds undergo intramolecular cyclization to form dibenzocyclohexadienes and that steric interactions between the methyl substituents leads to an increase in the rate of intramolecular cyclization, which is in contrast to what was observed for lignan di-catechols. The rate of cyclization to form six-membered rings is 10-30 times more rapid than formation of eight membered rings and the dibenzocyclohexadienes also prevent in vitro aggregation of α-synuclein.

In vitro hepatic metabolism of the natural product quebecol.

Quebecol (2,3,3-tri-(3-methoxy-4-hydroxyphenyl)-1-propanol) is a polyphenolic compound, which is formed during maple syrup production from Acer spp. Quebecol bears structural similarities to the chemotherapy drug tamoxifen, which has led to synthesis of structural analogues and investigations into their pharmacological properties, however there are no reports on the hepatic metabolism of quebecol.This interest in therapeutic properties spurred us to investigate the in vitro microsomal Phase I and II metabolism of quebecol. We were unable to detect any P450 metabolites for quebecol in either human liver microsomes (HLM) or rat liver microsomes (RLM). In contrast we observed marked formation of three glucuronide metabolites in both RLM and HLM, suggesting that clearance via Phase II pathways is likely to predominate.To further understand the hepatic contribution to first-pass glucuronidation we have validated an HPLC method following FDA and EMA guidelines (selectivity, linearity, accuracy, and precision) to quantify quebecol in microsomes. In vitro enzyme kinetics were performed for quebecol glucuronidation by HLM including 8 concentrations from 5-30 µM. We determined a Michaelis-Menten constant (KM) of 5.1 µM, intrinsic clearance (Clint,u) of 0.038 ± 0.001 mL/min/mg, and maximum velocity (Vmax) of 0.22 ± 0.01 µmol/min/mg.

Cerebral effects of glucagon-like peptide-1 receptor blockade before and after Roux-en-Y gastric bypass surgery in obese women: A proof-of-concept resting-state functional MRI study.

AIM: To assess the effects of Roux-en-Y gastric bypass surgery (RYGB)-related changes in glucagon-like peptide-1 (GLP-1) on cerebral resting-state functioning in obese women. MATERIALS AND METHODS: In nine obese females aged 40-54 years in the fasted state, we studied the effects of RYGB and GLP-1 on five a priori selected networks implicated in food- and reward-related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). RESULTS: Before surgery, GLP-1 receptor blockade (using exendin9-39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP-1 receptor blockade had a larger effect on connectivity in this region than GLP-1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. CONCLUSIONS: These findings suggest GLP-1 involvement in resting-state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP-1-induced changes in resting-state connectivity in RYGB-mediated weight loss and appetite control.

Anosognosia for memory in dementia with Lewy bodies compared with Alzheimer's disease.

OBJECTIVES: Anosognosia is the inability to recognize one's own symptoms. Although dementia with Lewy bodies (DLB) is the second most common degenerative dementia, there is little evidence of memory deficit awareness in this condition. The objectives of this research were to compare anosognosia between individuals with DLB and dementia due to Alzheimer's disease (AD) and to evaluate whether medial temporal atrophy, a marker of AD pathology, could help to explain different rates of anosognosia in DLB and dementia due to AD. METHODS/DESIGN: This is a cross-sectional study that took place at the Memory Clinic of D'Or Institute for Research and Education (IDOR). Twenty individuals with DLB and 20 with dementia due to AD were included in this study. We assessed anosognosia for memory using an index derived from subjective memory complaints (using the Memory Complaint Questionnaire) and from the performance in memory neuropsychological testing (Rey Auditory Verbal Learning Test). Thirty-one participants also underwent brain Magnetic Resonance Imaging to evaluate hippocampal atrophy with a visual scale (MTA-score [medial temporal atrophy score]). RESULTS: There was no significant difference between groups regarding age, years of education, sex or time of disease. Individuals with DLB had a higher index of anosognosia than dementia due to AD (2.92 and 1.87; p = 0.024), meaning worse awareness of memory deficits. MTA-score was slightly higher in dementia due to AD than in DLB, albeit without statistical significance. CONCLUSION: Our study was the first to demonstrate that anosognosia for memory is worse in DLB than in dementia due to AD. This finding supports the hypothesis that anosognosia in DLB is a heterogeneous phenomenon.

Cortical and subcortical gray matter structural alterations in normoglycemic obese and type 2 diabetes patients: relationship with adiposity, glucose, and insulin.

Type 2 diabetes (T2DM) is associated with structural cortical and subcortical alterations, although it is insufficiently clear if these alterations are driven by obesity or by diabetes and its associated complications. We used FreeSurfer5.3 and FSL-FIRST to determine cortical thickness, volume and surface area, and subcortical gray matter volume in a group of 16 normoglycemic obese subjects and 28 obese T2DM patients without clinically manifest micro- and marcoangiopathy, and compared them to 31 lean normoglycemic controls. Forward regression analysis was used to determine demographic and clinical correlates of altered (sub)cortical structure. Exploratively, vertex-wise correlations between cortical structure and fasting glucose and insulin were calculated. Compared with controls, obese T2DM patients showed lower right insula thickness and lower left lateral occipital surface area (PFWE < 0.05). Normoglycemic obese versus controls had lower thickness (PFWE < 0.05) in the right insula and inferior frontal gyrus, and higher amygdala and thalamus volume. Thalamus volume and left paracentral surface area were also higher in this group compared with obese T2DM patients. Age, sex, BMI, fasting glucose, and cholesterol were related to these (sub)cortical alterations in the whole group (all P < 0.05). Insulin were related to temporal and frontal structural deficits (all PFWE < 0.05). Parietal/occipital structural deficits may constitute early T2DM-related cerebral alterations, whereas in normoglycemic obese subjects, regions involved in emotion, appetite, satiety regulation, and inhibition were affected. Central adiposity and elevated fasting glucose may constitute risk factors.

Association of Androgenic Regulation and MicroRNAs in Acinar Adenocarcinoma of Prostate.

BACKGROUND: Prostate cancer represents 3.8% of cancer deaths worldwide. For most prostate cancer cells to grow, androgens need to bind to a cellular protein called the androgen receptor (AR). This study aims to demonstrate the expression of five microRNAs (miRs) and its influence on the AR formation in patients from the northern region of Brazil. MATERIAL AND METHODS: Eighty-four tissue samples were investigated, including nodular prostatic hyperplasia (NPH) and acinar prostatic adenocarcinoma (CaP). Five miRs (27a-3p, 124, 130a, 488-3p, and 506) were quantified using the TaqMan® Real Time PCR method and AR was measured using Western blotting. RESULTS: Levels of miRs 124, 130a, 488-3p, and 506 were higher in NPH samples. Conversely, in the CaP cases, higher levels of miR 27a-3p and AR were observed. CONCLUSION: In the future, these microRNAs may be tested as markers of CaP at the serum level. The relative expression of AR was 20% higher in patients with prostate cancer, which suggests its potential as a biomarker for prostate malignancy.

Structural Gray and White Matter Correlates of Awareness in Alzheimer's Disease.

BACKGROUND: Unawareness of disease is a common feature of Alzheimer's disease (AD), but few studies explored its neural correlates. Additionally, neural correlates according to the object of awareness are unexplored. OBJECTIVE: To investigate structural brain correlates in relation to different objects of awareness. METHODS: 27 people with AD underwent MRI scanning on a 3T Siemens Prisma. T1-MPRAGE was used to investigate cortical thickness and white matter microstructure was defined by DTI as fractional anisotropy, mean, axial, and radial diffusivity. Preprocessing used FreeSurfer6.0, ExploreDTI, and FSL-TBSS. Awareness of disease, cognitive deficits, emotional state, relationships, and functional capacity were assessed with the short version of the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia. Voxel-wise correlations between brain structure and awareness were determined by FSL-PALM. Analyses were corrected for multiple comparisons using Threshold Free Cluster Enhancement and FWE. RESULTS: Lower left hemisphere cortical thickness was related to poorer disease awareness uncorrected and corrected for age, sex, and MMSE. In the uncorrected model, mainly right-sided, but also left temporal lower cortical thickness was related to decreased awareness of cognitive deficits. Correcting for age, sex, and MMSE eliminated correlations for the right hemisphere, but extensive correlations in the left hemisphere remained. For white matter integrity, higher right hemisphere MD was related to lower cognitive awareness deficits, and lower FA was related to lower functional capacity awareness. CONCLUSION: Findings suggest that extensive regions of the brain are linked to self-awareness, with particular frontal and temporal alterations leading to unawareness, in agreement with theoretical models indicating executive and mnemonic forms of anosognosia in AD.

Mild Cognitive Impairment or Attention-Deficit/Hyperactivity Disorder in Older Adults? A Cross Sectional Study.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent neurodevelopmental condition, which may be associated with life-enduring cognitive dysfunction. It has been hypothesized that age-related cognitive decline may overlap with preexisting deficits in older ADHD patients, leading to increased problems to manage everyday-life activities. This phenomenon may mimic neurodegenerative disorders, in particular Mild Cognitive Impairment (MCI). This cross-sectional study aims to assess cognitive and behavioral differences between older subjects with ADHD and MCI. Methods: A total of 107 older participants (41 controls; 40 MCI and 26 ADHD; mean age = 67.60 ± 7.50 years; mean schooling = 15.14 ± 2.77 years; 65.4% females) underwent clinical, cognitive, and behavioral assessments by a multidisciplinary team at the Memory Clinic, D'Or Institute for Research and Education, Rio de Janeiro, Brazil. Mean scores in neuropsychological tasks and behavioral scales were compared across groups. Results: Participants with ADHD showed poorer performances than controls in episodic memory and executive function with large effect-sizes. Performances were comparable between MCI and ADHD for all domains. Discussion: MCI and ADHD in older individuals are dissociated clinical entities with overlapping cognitive profiles. Clinicians ought to be aware of these converging phenotypes to avoid misdiagnosis.

Network analysis of narrative discourse and attention-deficit hyperactivity symptoms in adults.

Previous research investigating language in attention-deficit hyperactivity disorder (ADHD) has demonstrated several deficits in many aspects. However, no previous study employed quantitative methodology providing objective measures that could be compared among different studies with diverse samples. To fill this gap, we used network analysis to investigate how ADHD symptomatology impacts narrative discourse, a complex linguistic task considered to be an ecological measure of language. Fifty-eight adults (34 females and 24 males) with a mean age of 26 years old and a mean of 17 years of educational level were administered the Adult Self-Rating Scale for ADHD symptomatology. They also completed the State-Trait Anxiety Inventory, the Beck Depression Inventory and the Urgency, Premeditation, Perseverance, Sensation Seeking Behavior Scale. Intelligence quotient was calculated. Individuals were asked to tell a story based on a wordless picture book. Speech was recorded and transcribed as an input to SpeechGraphs software. Parameters were total number of words (TNW), number of loops of one node (L1), repeated edges (RE), largest strongly connected component (LSC) and average shortest path (ASP). Verbosity was controlled. Statistical analysis was corrected for multiples comparisons and partial correlations were performed for confounding variables. After controlling for anxiety, depression, IQ, and impulsiveness ADHD symptomatology was positively correlated with L1 and negatively correlated with LSC. TNW was positively correlated with ADHD symptoms. In a subdomain analysis, both inattention and hyperactivity-impulsivity were negatively correlated with LSC. Only hyperactivity-impulsivity positively correlated with TNW and L1. Results indicated a correlation between ADHD symptoms and lower connectedness in narrative discourse (as indicated by higher L1 and lower LSC), as well as higher total number of words (TNW). Our results suggest that the higher the number of ADHD symptoms, the less connectivity among words, and a higher number of words in narrative discourse.

Inter-method and anatomical correlates of episodic memory tests in the Alzheimer's Disease spectrum.

BACKGROUND: Episodic memory impairments have been described as initial clinical findings in the Alzheimer's Disease (AD) spectrum, which could be associated with the presence of early hippocampal dysfunction. However, correlates between performances in neuropsychological tests and hippocampal volumes in AD were inconclusive in the literature. Divergent methods to assess episodic memory have been depicted as a major source of heterogeneity across studies. METHODS: We examined correlates among performances in three different delayed-recall tasks (Rey-Auditory Verbal-Learning Test-RAVLT, Logical Memory and Visual Reproduction subtests from the Wechsler Memory Scale) and fully-automated volumetric measurements of the hippocampus (estimated using Neuroquant®) of 83 older subjects (47 controls, 27 Mild Cognitive Impairment individuals and 9 participants with Dementia due to AD). RESULTS: Inter-method correlations of episodic memory performances were at most moderate. Scores in the RAVLT predicted up to 48% of variance in HOC (Hippocampal Occupancy Score) among subjects in the AD spectrum. DISCUSSION: Tests using different stimuli (verbal or visual) and presenting distinct designs (word list, story or figure learning) may assess divergent aspects in episodic memory, with heterogeneous anatomical correlates. CONCLUSIONS: Different episodic memory tests might not assess the same construct and should not be used interchangeably. Scores in RAVLT may correlate with the presence of neurodegeneration in AD.

Análise da tromboprofilaxia em pacientes cirúrgicos internados no Hospital do Servidor Público Municipal ­ SP / Thromboprophylaxis analysis in surgical patients hospitalized at Hospital do Servidor Público Municipal ­ SP

INTRODUÇÃO: O tromboembolismo é a principal causa de morte evitável no ambiente hospitalar e está associado a distúrbios de circulação corpórea alusivos a Tríade de Virchow, a qual é composta pela estase venosa, estado de hipercoagulabilidade e lesão endotelial. Estes três fatores estão intimamente relacionados ao paciente enfermo hospitalizado e restrito ao leito. Diante disso, existem indicações formais para realização da tromboprofilaxia, entretanto, sabe-se que, mesmo havendo essas indicações, a tromboprofilaxia ainda é subutilizada, sobretudo em se tratando de pacientes cirúrgicos. OBJETIVO: Analisar a aplicação da tromboprofilaxia em pacientes cirúrgicos internados no Hospital do Servidor Público Municipal. METODOLOGIA: Trata-se de um estudo de coorte retrospectiva em que a execução do trabalho se deu por meio da análise dos dados de prontuários de pacientes internados pelas clínicas do Pronto-Socorro, Retaguarda e Gastrocirurgia. Os dados coletados foram mensurados através do escore de Caprini a fim de analisar a indicação da trombrofilaxia. RESULTADOS: Respeitando os critérios de inclusão foram analisados um total de 311 prontuários, sendo destes 127 correspondentes ao sexo feminino e 184 ao sexo masculino, sendo 120 paciente internados pela gastrocirurgia, 160 pelo pronto-socorro e 31 pela retaguarda, tendo a faixa etária mais prevalente entre os 41 aos 61 anos. Após análise das características de acordo com o escore de Caprini, notou-se que 161 eram enquadrados no grupo de baixo risco, 120 em risco moderado e 4 em alto risco para o desenvolvimento de eventos tromboembólicos. Foram observados um total de 10 casos que tiveram como desfecho o tromboembolismo. DISCUSSÃO: Após a análise de resultados, notou-se que mesmo com as indicações formais de tromboprofilaxia a mesma foi subutilizada e apesar do número de eventos tromboembólicos não ser significativo ao se levar em conta o tamanho da amostra, em números absolutos, foi possível evidenciar um quantitativo menor de indivíduos que desenvolveram tromboembolismo na população que fez uso da profilaxia em comparação aos que não fizeram uso da profilaxia. CONCLUSÃO: O estudo permitiu observar a relação direta entre o alto risco para o desenvolvimento do tromboembolismo e a necessidade da tromboprofilaxia, demonstrando que esta, apesar de subutilizada no Hospital do Servidor Público Municipal, precisa ser executada de maneira racional, observando as particularidades e condições de cada paciente internado a fim de evitar desfechos desfavoráveis. Palavras-chave: Tromboembolia Venosa. Embolia Pulmonar. Coagulação Sanguínea. Anticoagulantes.