Synthesis and 2D-QSAR studies of neolignan-based diaryl-tetrahydrofuran and -furan analogues with remarkable activity against Trypanosoma cruzi and assessment of the trypanothione reductase activity.

Two series of diaryl-tetrahydrofuran and -furan were synthesised and screened for anti-trypanosomal activity against trypomastigote and amastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. Based on evidence that modification of a natural product may result in a more effective drug than the natural product itself, and using known neolignan inhibitors veraguensin 1 and grandisin 2 as templates to synthesise simpler analogues, remarkable anti-trypanosomal activity and selectivity were found for 3,5-dimethoxylated diaryl-furan 5c and 2,4-dimethoxylated diaryl-tetrahydrofuran 4e analogues with EC50 0.01 µM and EC50 0.75 µM, respectively, the former being 260-fold more potent than veraguensin 1 and 150-fold better than benznidazole, the current available drugs for Chagas disease treatment. The ability of the most potent anti-trypanosomal compounds to penetrate LLC-MK2 cells infected with T. cruzi amastigotes parasite was tested, which revealed 4e and 5e analogues as the most effective, causing no damage to mammalian cells. In particular, the majority of the derivatives were non-toxic against mice spleen cells. 2D-QSAR studies show the rigid central core and the position of dimethoxy-aryl substituents dramatically affect the anti-trypanosomal activity. The mode of action of the most active anti-trypanosomal derivatives was investigated by exploring the anti-oxidant functions of Trypanothione reductase (TR). As a result, diarylfuran series displayed the strongest inhibition, highlighting compounds 5d-e (IC50 19.2 and 17.7 µM) and 5f-g (IC50 8.9 and 7.4 µM), respectively, with similar or 2-fold higher than the reference inhibitor clomipramine (IC50 15.2 µM).

Mortality from dementia in a community-dwelling Brazilian population.

BACKGROUND: The influence of dementia on mortality has not yet been reported for a Latin American country. OBJECTIVES: To evaluate the influence of dementia on mortality of a community-dwelling elderly population in Brazil, and to verify the extent to which the diagnosis of dementia is reported on death certificates. METHODS: A cohort of 1,656 individuals, aged 65 and over, was screened for dementia at their domiciles, in 1997. The same population was re-evaluated in 2000, and information on deaths was obtained from relatives and from the municipal obituary service. Kaplan-Meier curves were used for the survival analysis, and the mortality risk ratio (MMR) was calculated using Cox proportional hazards models. RESULTS: We obtained data from 1,393 subjects, corresponding to 84.1% of the target population. The number of deaths was 58 (51.3%) among the patients with dementia and 163 (12.7%) among those without dementia in 1997 (p <0.0001). Dementia and Alzheimer's disease (AD) decreased survival, with hazards ratios of 5.16 [95% Confidence Interval (CI): 3.74-7.12] for dementia and 4.76 (95% CI: 3.16-7.18) for AD. The Cox proportional hazards model identified dementia (MMR=3.92, 95% CI: 2.80-5.48) as the most significant predictor of death, followed by age, history of stroke, complaints of visual impairment and heart failure and by severe arterial hypertension in the baseline evaluation. Dementia and/or AD were mentioned in only 12.5% of the death certificates of individuals with dementia. CONCLUSIONS: Dementia causes a significant decrease in survival, and the diagnosis of dementia is rarely reported on death certificates in Brazil.

Hyperphosphorylated tau protein in the cerebrospinal fluid of patients with Alzheimer's disease and other dementias: preliminary findings.

Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and tau-associated neurofibrillary tangles in the cerebral tissue. The search for antemortem biomarkers is intense including analysis of cerebrospinal fluid (CSF) beta-amyloid and tau proteins concentrations seeking for an accurate and early diagnosis. Levels of hyperphosphorylated tau at threonine 181 were measured in the CSF of 34 patients with AD (19 with senile AD - SAD and eight with presenile AD - PSAD) and seven with other dementias (OD). The levels of CSF phosphotau were significantly higher in the AD patients compared to OD (AUC 0.812), with no association with severity of dementia, age of onset, duration of the disease or scores in the Mini-Mental State Examination. There were no differences of phosphotau levels between SAD and PSAD patients. These findings corroborate some previous studies and indicate that CSF phosphotau may help to differentiate AD from other dementias.

Hyperphosphorylated tau protein in the cerebrospinal fluid of patients with Alzheimer's disease and other dementias: preliminary findings

A doença de Alzheimer (DA) se caracteriza pelo achado anátomo-patológico de acúmulo de placas senis e emaranhados neurofibrilares associados à proteína tau no tecido cerebral. A pesquisa por marcadores biológicos antemortem está focada nas concentrações das proteínas b-amilóide e tau no líquido cefalorraqueano (LCR) objetivando um diagnóstico mais precoce e acurado da doença. Os níveis de proteína tau hiperfosforilada no sítio 181 foram determinados no LCR de 34 pacientes com DA (19 com DA senil - DAS e oito com DA pré-senil -DAPS) e sete pacientes com outras demências (OD). Os níveis de fosfotau foram significativamente mais elevados em pacientes com DA quando comparados com OD (AUC 0,812), sem relação com gravidade da demência, idade de início, duração da doença e escores do Mini-Exame do Estado Mental. Não foram observadas diferenças entre os níveis de fosfotau em pacientes com DAS e DAPS. Estes achados corroboram os dados encontrados em estudos prévios e indicam que o nível de fosfotau no LCR dos pacientes pode colaborar na diferenciação da DA com outras demências.

Prevalence of potentially reversible dementias in a dementia outpatient clinic of a tertiary university-affiliated hospital in Brazil

The importance of investigating the etiology for dementia lies in the possibility of treating potentially reversible dementias. The aims of this retrospective study are to determine the prevalence of potentially reversible dementias among 454 outpatients seen at the Cognitive and Behavioral Neurology Unit, Hospital das Clínicas, São Paulo University School of Medicine - Brazil, between the years of 1991 and 2001, and observe their evolution in follow-up. Among the initial 454 patients, 275 fulfilled the DSM-IV criteria for dementia. Alzheimer's disease was the most frequent diagnosis (164 cases; 59.6 percent). Twenty-two cases (8.0 percent) of potentially reversible dementia were observed, the most frequent diagnoses being neurosyphilis (nine cases) and hydrocephalus (six cases). Full recovery was observed in two patients and partial recovery in 10 patients. Two cases were not treated and eight cases were lost on follow-up. The prevalence found in the present study falls within the range reported in previous studies (0-30 percent)

Prevalence of potentially reversible dementias in a dementia outpatient clinic of a tertiary university-affiliated hospital in Brazil.

The importance of investigating the etiology for dementia lies in the possibility of treating potentially reversible dementias. The aims of this retrospective study are to determine the prevalence of potentially reversible dementias among 454 outpatients seen at the Cognitive and Behavioral Neurology Unit, Hospital das Clínicas, São Paulo University School of Medicine-Brazil, between the years of 1991 and 2001, and observe their evolution in follow-up. Among the initial 454 patients, 275 fulfilled the DSM-IV criteria for dementia. Alzheimer's disease was the most frequent diagnosis (164 cases; 59.6%). Twenty-two cases (8.0%) of potentially reversible dementia were observed, the most frequent diagnoses being neurosyphilis (nine cases) and hydrocephalus (six cases). Full recovery was observed in two patients and partial recovery in 10 patients. Two cases were not treated and eight cases were lost on follow-up. The prevalence found in the present study falls within the range reported in previous studies (0-30%).