Investigation on formulation parameters of donepezil HCl loaded solid lipid nanoparticles

Abstract Donepezil-HCl is a member of the acetylcholinesterase inhibitors that is indicated for the symptomatic treatment of Alzheimer's disease (AD) and has many side effects. In this study, to reduce the side effects of Donepezil-HCl and increase the penetration of the drug through the blood-brain barrier, we aimed to design a solid lipid nanoparticle (SLN) formulation. The effects of the different formulation parameters, such as homogenization speed, sonication time, lipid and drug concentration, surfactant type and concentration, and volume of the aqueous phase, were assessed for optimization. The particle size and PDI increased with increasing lipid concentration but decreased with increasing amounts of surfactant (Tween 80) and co-surfactant (lecithin). When the homogenization rate and sonication time increased, the particle size decreased and the encapsulation efficiency increased. The optimized formulation exhibited particle size, PDI, encapsulation efficiency, and zeta potential of 87.2±0.11 nm; 0.22±0.02; 93.84±0.01 %; -17.0±0.12 mV respectively. The in vitro release investigation revealed that approximately 70% of Donepezil-HCl was cumulatively released after 24 hours. TEM analysis proved that spherical and smooth particles were obtained and formulations had no toxic effect on cells. The final optimized formulation could be a candidate for Donepezil-HCl application in Alzheimer's treatment with reduced side effects and doses for patients

Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease / 神经科学通报·英文版

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

Knock-down of ROCK2 gene improves cognitive function and reduces neuronal apoptosis in AD mice by promoting mitochondrial fusion and inhibiting its division / 细胞与分子免疫学杂志

Objective To explore the effect of knocking down Rho-associated coiled-coil kinase (ROCK2) gene on the cognitive function of amyloid precursor protein/presenilin-1 (APP/PS1) double transgenic mice and its mechanism. Methods APP/PS1 double transgenic mice were randomly divided into AD model group (AD group), ROCK2 gene knock-down group (shROCK2 group), ROCK2 gene knock-down control group (shNCgroup), and wild-type C57BL/6 mice of the same age served as the wild-type control (WT group). Morris water maze and Y maze were employed to test the cognitive function of mice. Neuron morphology was detected by Nissl staining. Immunofluorescence histochemical staining was used to detect the expression of phosphorylated dynamin-related protein 1 (p-Drp1) and mitochondrial fusion 1 (Mfn1). Western blot analysis was used to detect the expression ROCK2, cleaved-caspase-3 (c-caspase-3), B-cell lymphoma 2 (Bcl2), Bcl2-related protein X (BAX), p-Drp1, mitochondrial fission 1 (Fis1), optic atrophy 1 (OPA1), Mfn1 and Mfn2. Results Compared with AD group mice, the expression of ROCK2 in shROCK2 group mice was significantly reduced; the cognitive function was significantly improved with the number of neurons in the hippocampal CA3 and DG areas increasing, and nissl bodies were deeply stained; the expression of c-caspase-3 and BAX was decreased, while the expression of Bcl2 was increased; the expression of mitochondrial division related proteins p-Drp1 and Fis1 were decreased, while the expression of mitochondrial fusion-related proteins OPA1, Mfn1 and Mfn2 were increased. Conclusion Knock-down of ROCK2 gene can significantly improve the cognitive function and inhibit the apoptosis of nerve cells of APP/PS1 mice. The mechanism may be related to promoting mitochondrial fusion and inhibiting its division.

C/EBPβ/AEP Signaling Drives Alzheimer's Disease Pathogenesis / 神经科学通报·英文版

Alzheimer's disease (AD) is the most common type of dementia. Almost two-thirds of patients with AD are female. The reason for the higher susceptibility to AD onset in women is unclear. However, hormone changes during the menopausal transition are known to be associated with AD. Most recently, we reported that follicle-stimulating hormone (FSH) promotes AD pathology and enhances cognitive dysfunctions via activating the CCAAT-enhancer-binding protein (C/EBPβ)/asparagine endopeptidase (AEP) pathway. This review summarizes our current understanding of the crucial role of the C/EBPβ/AEP pathway in driving AD pathogenesis by cleaving multiple critical AD players, including APP and Tau, explaining the roles and the mechanisms of FSH in increasing the susceptibility to AD in postmenopausal females. The FSH-C/EBPβ/AEP pathway may serve as a novel therapeutic target for the treatment of AD.

Disrupted Maturation of Prefrontal Layer 5 Neuronal Circuits in an Alzheimer's Mouse Model of Amyloid Deposition / 神经科学通报·英文版

Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid β (Aβ)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22-30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.

Alterations of Audiovisual Integration in Alzheimer's Disease / 神经科学通报·英文版

Audiovisual integration is a vital information process involved in cognition and is closely correlated with aging and Alzheimer's disease (AD). In this review, we evaluated the altered audiovisual integrative behavioral symptoms in AD. We further analyzed the relationships between AD pathologies and audiovisual integration alterations bidirectionally and suggested the possible mechanisms of audiovisual integration alterations underlying AD, including the imbalance between energy demand and supply, activity-dependent degeneration, disrupted brain networks, and cognitive resource overloading. Then, based on the clinical characteristics including electrophysiological and imaging data related to audiovisual integration, we emphasized the value of audiovisual integration alterations as potential biomarkers for the early diagnosis and progression of AD. We also highlighted that treatments targeted audiovisual integration contributed to widespread pathological improvements in AD animal models and cognitive improvements in AD patients. Moreover, investigation into audiovisual integration alterations in AD also provided new insights and comprehension about sensory information processes.

Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology / 神经科学通报·英文版

The physiological functions of endogenous amyloid-β (Aβ), which plays important role in the pathology of Alzheimer's disease (AD), have not been paid enough attention. Here, we review the multiple physiological effects of Aβ, particularly in regulating synaptic transmission, and the possible mechanisms, in order to decipher the real characters of Aβ under both physiological and pathological conditions. Some worthy studies have shown that the deprivation of endogenous Aβ gives rise to synaptic dysfunction and cognitive deficiency, while the moderate elevation of this peptide enhances long term potentiation and leads to neuronal hyperexcitability. In this review, we provide a new view for understanding the role of Aβ in AD pathophysiology from the perspective of physiological meaning.

Quantitative Characterization of the Chemical Space Governed by Human Carbonic Anhydrases and selenium-containing derivatives of solfonamides

Abstract Due to the fact that different isoforms of carbonic anhydrase play distinct physiological roles, their diseases/disorders involvement are different as well. Involvement in major disorders such as glaucoma, epilepsy, Alzheimer's disease, obesity and cancers, have turned carbonic anhydrase into a popular case study in the field of rational drug design. Since carbonic anhydrases are highly similar with regard to their structures, selective inhibition of different isoforms has been a significant challenge. By applying a proteochemometrics approach, herein the chemical interaction space governed by acyl selenoureido benzensulfonamides and human carbonic anhydrases is explored. To assess the validity, robustness and predictivity power of the proteochemometrics model, a diverse set of validation methods was used. The final model is shown to provide valuable structural information that can be considered for new selective inhibitors design. Using the supplied information and to show the applicability of the constructed model, new compounds were designed. Monitoring of selectivity ratios of new designs shows very promising results with regard to their selectivity for a specific isoform of carbonic anhydrase.

Impact of pharmacist intervention in patients with Alzheimer's disease

Abstract To assess the therapy relative to indication, effectiveness, safety and adherence in patients with Alzheimer's disease (AD). An interventional, prospective, non-randomized study was conducted in a single secondary care center in Brazil. The pharmacist-led medication therapy management (MTM) was conducted to detect drug-related problems (DRPs) at baseline and after six months of intervention. The health status outcomes (i.e. cognitive screening tests; levels of glucose; total cholesterol; triglycerides; thyroid stimulating hormone; serum free thyroxine and blood pressure) were measured. 66 patients with AD were included, of whom 55 patients completed the follow-up of six months. 36 patients (36/55) were non-adherent to AD drug therapy. Out of detected 166 DRPs, 116 were solved. Four patients were withdrawn from the AD protocol due to resolution of prodromal symptoms. On the conclusion of the study, the MTM improved and controlled blood pressure, glucose, total cholesterol, triglycerides levels (p<0.05). The pharmacist-led MTM was effective in solving 69.8% of DRPs, improving and controlling the clinical parameters evaluated

Polysaccharide Krestin Prevents Alzheimer's Disease-type Pathology and Cognitive Deficits by Enhancing Monocyte Amyloid-β Processing / 神经科学通报·英文版

Deficits in the clearance of amyloid β protein (Aβ) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aβ by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβ clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aβ uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aβ deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβ clearance by blood monocytes and alleviating AD-like pathology.

Chronic hypoperfusion due to intracranial large artery stenosis is not associated with cerebral β-amyloid deposition and brain atrophy / 中华医学杂志(英文版)

BACKGROUND@#Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease (AD). However, there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology. We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.@*METHODS@#We enrolled a group of cognitively normal patients (median age: 64 years) with unilateral chronic cerebral hypoperfusion. Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion. 11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.@*RESULTS@#The median age of the 10 participants, consisting of 4 males and 6 females, was 64 years (47-76 years). We found that there were no differences in standard uptake ratios of the cortex (volume of interest [VOI]: P = 0.721, region of interest [ROI]: P = 0.241) and grey/white ratio (VOI: P = 0.333, ROI: P = 0.445) and brain atrophy indices (Bicaudate, Bifrontal, Evans, Cella, Cella media, and Ventricular index, P > 0.05) between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.@*CONCLUSION@#Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebral β-amyloid deposition and neurodegeneration in humans.

Factors Influencing Alzheimer's Disease Risk: Whether and How They are Related to the APOE Genotype / 神经科学通报·英文版

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease featuring progressive cognitive impairment. Although the etiology of late-onset AD remains unclear, the close association of AD with apolipoprotein E (APOE), a gene that mainly regulates lipid metabolism, has been firmly established and may shed light on the exploration of AD pathogenesis and therapy. However, various confounding factors interfere with the APOE-related AD risk, raising questions about our comprehension of the clinical findings concerning APOE. In this review, we summarize the most debated factors interacting with the APOE genotype and AD pathogenesis, depict the extent to which these factors relate to APOE-dependent AD risk, and discuss the possible underlying mechanisms.

Estado nutricional de indivíduos com Comprometimento Cognitivo Leve e Doença de Alzheimer em relação ao Selênio e sua associação com parâmetros que predispõem ao declínio cognitivo / Nutritional status of subjects with mild cognitive impairment and Alzheimer's disease in relation to selenium and its association with paramenters that predispose to cognitive decline

A Doença de Alzheimer (DA) é a principal forma de demência e um dos grandes desafios no sistema de saúde do século 21. O Comprometimento Cognitvo Leve (CCL) é um estágio que antecede a DA e que compartilha algumas vias metabólicas em comum. A fisiopatologia da DA é caracterizada pela ampla morte neuronal e pela presença de placas neuríticas e emaranhados neurofibrilares, respectivamente relacionadas ao acúmulo de peptídeo beta amiloide (Aß) em tecidos cerebrais e alterações no citoesqueleto que se originam da hiperfosforilação da proteína tau nos neurônios. Algumas linhas de evidência sustentam a hipótese de que o estresse oxidativo, nitrosativo e a inflamação tenham um papel importante na patogênese tanto do DA como do CCL. O selênio, mineral essencial ao ser humano, encontra-se incorporado ao sítio ativo de 25 selenoproteínas, das quais pelo menos um terço apresenta papel antioxidante, além de potencialmente modularem o sistema inflamatório. Deste modo, o estado nutricional adequado dos indivíduos relativo ao selênio, parece exercer efeito neuroprotetor, reduzindo o risco para o CCL e DA e retardando a progressão destas doenças. A entrega de selênio para o cérebro se dá pela interação da selenoproteína P (SELENOP) com o receptor de apolipoproteína E2 (ApoER2). A apolipoproteína E (ApoE) também interage com o ApoER2 no metabolismo de lipídeos. Assim, pode-se pensar que indivíduos portadores do polimorfismo do gene da apolipoproteína E ε4 (APOE ε4), o principal polimorfismo genético para o aumento no risco de desenvolvimento de DA, possam ter essa entrega de selênio prejudicada para o cérebro uma vez que os receptores ApoER2 dos portadores do polimorfismo de APOE ε4 são sequestrados para compartimentos intracelulares, sendo menos expressos na membrana plasmática e portanto diminuindo a interação com a SELENOP. Este trabalho teve por objetivo avaliar se a distribuição do selênio no plasma e líquor de indivíduos portadores de CCL e DA é afetada pelo alelo APOE ε4, avaliar se o estado nutricional do indivíduo em relação ao selênio afeta marcadores de assinatura biológica para DA (peptídeo beta amilóide, proteína tau e proteína tau fosforilada) e concentrações de citocinas inflamatórias. Para tanto, foram selecionadas amostras de plasma e líquor do banco de material biológico do Instituto de Psiquiatria da FMUSP, sendo 14 indivíduos do grupo CCL, 28 indivíduos do grupo DA e 28 indivíduos controles, de ambos os gêneros, com idade acima de 60 anos e residentes na cidade de São Paulo. Foram avaliados os seguintes marcadores: concentrações de selênio no plasma e líquor, concentrações SELENOP no plasma e líquor, citocinas inflamatórias, fator neurotrófico derivado do cérebro (BDNF) e marcadores de assinatura biológica para DA. Não foi evidenciada diferença entre os três diferentes grupos em relação ao selênio e a SELENOP da mesma forma que não houve influência do genótipo APOE ε4 nas concentrações de selênio e SELENOP, porém houve uma tendência de menores concentrações de selênio plasmático nos carreadores do alelo APOE ε4. Também houve uma tendência a uma menor pontuação nos testes MMSE e CAMCOG em indivíduos com menores concentrações plasmáticas de selênio. Não se evidenciou que o estado nutricional dos indivíduos em relação ao selênio influencie as concentrações de marcadores para assinatura biológica para DA e de citocinas inflamatórias, com exceção da IL-10 que apresentou correlação positiva com SELENOP plasmática. A partir desses resultados, conclui-se que o estado nutricional dos indivíduos relativo ao selênio parece não ter influencia significativa em aspectos do CCL e DA e que sua distribuição não é alterada pelo genótipo APOE ε4

Alzheimer's disease (AD) is the main form of dementia and one of the major challenges in the healthcare system of the 21st century. Mild Cognitive Impairment (MCI) is a stage that precedes AD and shares common metabolic pathways. The pathophysiology of AD is characterized by extensive neuronal death, presence of neuritic plaques and neurofibrillary tangles, respectively related to the accumulation of amyloid beta peptide (Aß) in brain tissues and changes in the cytoskeleton that originate from hyperphosphorylation of the Tau protein in neurons. Some lines of evidence support the hypothesis that oxidative, nitrosative stress and inflammation play an important role in the pathogenesis of both AD and MCI. Selenium, an essential mineral to humans, is incorporated into the active site of 25 selenoproteins, of which at least one third has an antioxidant role, in addition to its potential in modulating the inflammatory system. Therefore, the appropriate nutritional status related to selenium seems to exert a neuroprotective effect, reducing the risk for MCI and AD and decreasing the progression of these diseases. Selenium is delivered to the brain by the interaction of selenoprotein P (SELENOP) with the ApoE2 receptor (ApoER2). Apolipoprotein E (ApoE) also interacts with ApoER2 in lipid metabolism. Thus, it can be speculated that individuals that carry apolipoprotein E ε4 gene (APOE ε4), the main genetic polymorphism that increases the risk of AD, may have impaired selenium delivery to the brain since ApoER2 receptors of the APOE ε4 carriers are sequestered to intracellular compartments, being less expressed in the plasma membrane decreasing its interaction with SELENOP. This study aimed to assess whether the distribution of selenium in the plasma and CSF of subjects with MCI and AD is affected by the APOE ε4 allele, evaluate whether the nutritional status of selenium affects biological signature markers for AD (amyloid beta peptide, tau protein and phosphorylated tau protein) and to asses the concentrations of inflammatory cytokines. For this purpose, plasma and cerebrospinal fluid (CSF) samples were selected from the biological material bank of the Institute of Psychiatry of FMUSP, with 14 subjects from the MCI group, 28 from the DA group and 28 from control subjects, both genders, aged over 60 years and São Paulo residents. The following markers were evaluated: selenium concentrations in plasma and CSF, SELENOP concentrations in plasma and CSF, inflammatory cytokines, brain-derived neurotrophic factor (BDNF) and biological signature for AD. There was no difference between the three different groups in relation to selenium and SELENOP; in addition, there was no influence of the APOE ε4 genotype on selenium and SELENOP concentrations, but there was a tendency towards lower plasma selenium concentrations in the APOE ε4 carriers. There was also a tendency for lower scores on the MMSE and CAMCOG tests in subjects with lower plasma selenium concentrations. It was not shown that selenium nutritional status influences the concentrations of biological signature for AD and inflammatory cytokines, with the exception of IL-10 which showed a positive correlation with plasma SELENOP. From these results, we concluded that selenium nutritional status does not seem to have a significant influence in aspects of MCI and DA and that its distribution is not altered by the APOE genotype ε4

Salivary biomarkers in Alzheimer´s disease / Biomarcadores salivales en la enfermedad de Alzheimer

The hypotheses currently considered the most likely causes of Alzheimer's disease (AD) are amyloid beta peptide deposition in the cerebral cortex and hyperphosphorylation of the Tau protein, with the consequent formation of neurofibrillary tangles. In clinical practice, although not accurate, AD diagnosis is based on the exclusion of other diseases, behavioural assessments and complementary examinations, such as imaging and blood tests. Advances in the field of biotechnology have created exciting prospects for the early detection of AD via biomarker assessment, which is considered a safer and more efficient procedure. Molecules recognised as biomarkers can be expressed in some body fluids, including cerebrospinal fluid, saliva and blood. The presence of amyloid beta peptide and Tau can be confirmed in saliva, which is also an easily and non-invasively collectable material with an accessible cost. The objective was evaluate the concentrations of the t-Tau protein and Ab42 peptide in the saliva of elderly individuals with and without dementia of the AD type Method: The objective of this case-control study, involving a total of 120 individuals, was to analyse whether a correlation exists between variations in the concentrations of the t-Tau and Ab42 biomarkers in the saliva of patients with confirmed AD and individuals in the inclusion group but without AD . We found that t-Tau expression in AD patients is significantly lower than that in individuals without AD, whereas the salivary concentration of Ab42 is higher in patients with AD but not significantly different from that of the group without AD. Conclusion: Thus, we demonstrate the feasibility of using salivary biomarkers as predictive markers for diagnosis of Alzheimer's disease.

Las hipótesis consideradas actualmente como las causas más probables de la enfermedad de Alzheimer (EA) son la deposición de péptido beta amiloide en la corteza cerebral y la hiperfosforilación de la proteína Tau, con la consiguiente formación de ovillos neurofibrilares. En la práctica clínica, aunque no es precisa, el diagnóstico de la EA se basa en la exclusión de otras enfermedades, evaluaciones de comportamiento y exámenes complementarios, como imágenes y análisis de sangre. Los avances en el campo de la biotecnología han creado interesantes perspectivas para la detección temprana de la EA a través de la evaluación de biomarcadores, que se considera un procedimiento más seguro y más eficiente. Las moléculas reconocidas como biomarcadores se pueden expresar en algunos fluidos corporales, incluidos el líquido cerebroespinal, la saliva y la sangre. La presencia del péptido beta amiloide (AB) y la proteína Tau (t-Tau) se puede confirmar en la saliva, que también es un material fácil y no invasivo de recolección con un costo accesible. El objetivo fue evaluar las concentraciones de la proteína t-Tau y el péptido Ab42 en la saliva de las personas de edad avanzada con y sin demencia del tipo de tipo EA. El estudio de casos y controles, se realizó en un total de 120 personas, para analizar si existe una correlación entre las variaciones en las concentraciones de los biomarcadores t-Tau y Ab42 en la saliva de pacientes con EA confirmada e individuos en el grupo de inclusión pero sin AD. Encontramos que la expresión de t-Tau en pacientes con EA es significativamente menor que en individuos sin EA, mientras que la concentración salival de Ab42 es mayor en pacientes con EA pero no significativamente diferente de la del grupo sin la enfermedad . Por lo tanto, se demuestra la viabilidad del uso de biomarcadores salivales como marcadores predictivos para el diagnóstico de la enfermedad de Alzheimer.

Micro and nanocrystalline cellulose based oral dispersible film; preparation and evaluation of in vitro/in vivo rapid release studies for donepezil

Oral fast-dispersible film was prepared by utlizing donepezil hydrochloride (drug) and various cellulose derivatives such as hydroxypropyl methyl cellulose (hypermellose) (HPMC), microcrystalline cellulose (MCC) and nanocrystalline cellulose (NCC) to treat Alzheimer's disease. NCC was synthesized by ultra-sonication method using MCC and this was converted to thinfilm formulation (NCC-F) using solvent casting technique. The interaction between the polymer and the drug was investigated by spectral analysis such as UV, FTIR, and 1H- NMR. FTIR confirmed that the compatibility of drug and polymer in ODF formulation. NCC-F has shown an average surface roughness of 77.04 nm from AFM and the average particle size of 300 nm from SEM analysis. Nano sized particle of NCC-F leads faster in vitro dissolution rate (94.53%) when compared with MCC-F and F3 formulation. Animal model (in vivo) studies of NCC-F formulation has reached peak plasma concentration (Cmax) up to 19.018 ng/mL in the span of (tmax) 4 h with greater relative bioavailability of 143.1%. These results suggested that high surface roughness with nanosized NCC-F formulation attained extended drug availability up to (t1/2) 70 h.

Primary age-related tauopathy in a Chinese cohort / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Primary age-related tauopathy (PART) is characterized by the presence of tau neurofibrillary tangles (NFTs) which are typically observed in Alzheimer's disease (AD) brains, with few or without β-amyloid (Aβ) plaques. The diagnosis of PART can be categorized into "definite" or "possible" depending on the amount of Aβ plaques. Definite PART is diagnosed when NFTs are observed and the Braak stage is ≤IV, with Thal Aβ Phase 0 (Crary et al., 2014). According to the neuropathological diagnostic criteria, we reported that PART was frequently observed in the Chinese population according to our findings from specimens in our brain bank, with 47% of brain bank subjects meeting the criteria for PART. There is no consensus on the nature of PART. It remains to be elucidated whether PART is an early form of AD or a novel tauopathy (Duyckaerts et al., 2015; Jellinger et al., 2015).

Structural Volume of Hippocampus and Alzheimers Disease

RESUMO Pesquisas recentes demonstram que o hipocampo apresenta uma redução de volume no final da idade adulta, mantendo uma estreita relação com o declínio cognitivo. A aquisição da imagem por diversos métodos de medição de volume nos leva a encontrar na ressonância magnética o método de destaque, pois permite quantificar o volume de determinadas estruturas cerebrais utilizando a reconstrução computadorizada tridimensional das imagens obtidas. OBJETIVOS Confirmar a existência de diferenças entre o volume hipocampal e o declínio cognitivo leve, doença de Alzheimer e cognição normal. MÉTODOS Levantamento bibliográfico de estudos que apresentassem dados referentes aos distúrbios da doença de Alzheimer, alterações macroscópicas cerebrais detectadas com softwares na ressonância magnética e segmentação. Foram adicionados estudos apenas da medição volumétrica do hipocampo, objetivando-se chegar a valores que possam estabelecer uma correlação do menor valor estrutural hipocampal e risco de desenvolvimento da doença. RESULTADOS Um total de 1.070 indivíduos foi analisado em seis estudos clínicos, demonstrando a relação da diminuição do hipocampo na neuroimagem, correlacionado com o comprometimento cognitivo leve e doença de Alzheimer. CONCLUSÕES O desenvolvimento de um valor padrão para esse fim seria bastante útil na coleta de dados, permitindo melhor compreensão de algumas alterações que podem ocorrer na cognição, determinar valores prognósticos e até, em um futuro próximo, fator de risco imagiológico para a doença.

Funcionalidade na doença de Alzheimer leve, moderada e grave: um estudo transversal / Functionality on mild, moderate and severe Alzheimer's disease: a cros-sectional study

Objetivo: Avaliar a funcionalidade de pacientes com Doença de Alzheimer (DA) residentes na comunidade, no município de Guarapuava ­ PR, região Sul do Brasil. Métodos: Foi realizado um estudo transversal, com pacientes com DA residentes na comunidade, no município de Guarapuava ­ PR. Os participantes foram classificados de acordo com a Escala Clínica de Demência em CDR 1 (DA leve), CDR 2 (DA moderada) e CDR 3 (DA severa). O estado mental foi avaliado através do Mini Exame do Estado Mental; as atividades básicas de vida diária (ABVD) através do Índice de Barthel e as atividades instrumentais de vida diária (AIVD) através do Índice de Lowton e Brody. Resultados: Foram avaliados 58 idosos com diagnóstico de DA, dos quais 14 (24,1%) estavam em CDR 1, 21 (36,2%) em CDR 2 e 23 (39,7%) em CDR 3. Houve diferença significativa entre os níveis de dependência para a realização das ABVD e AIVD entre todas as fases da DA (p <0,001), sendo que a dependência foi maior nos participantes estadeados em CDR 2 e CDR 3. Conclusão: O nível de dependência para a realização das atividades básicas e instrumentais de vida diária é maior nas fases mais avançadas da DA e a dependência para a realização das AIVD está presente em todas as fases da doença, sendo maior do que a dependência para a realização das ABVD desde a fase inicial da DA, sugerindo uma perda progressiva da funcionalidade

Objective: To evaluate the functionality of patients with Alzheimer's disease (AD) living in a community, in the city of Guarapuava PR, South of Brazil. Methods: A cross-sectional study was performed with patients with AD living in the community. Participants were classified according to Clinical Dementia Rating as CDR 1 (mild AD), CDR 2 (moderate AD) and CDR 3 (severe AD). The mental state was assessed by the Mini Mental State Examination; the basic activities of daily living (ADLs) was determined by the Barthel Index and instrumental activities of daily living (IADLs) via by Lowton and Brody Index. Results: 49 elderly patients with AD diagnosis were evaluated, 14 (24.1%) of which were classified as CDR 1, 21 (36.2%) as CDR 2, and 23 (39.7%) as CDR 3. There was a significant difference between the levels of dependence for the performance of the basic ADLs and IADLs among all phases of AD (p <0.001). The dependence was higher in both CDR 2 and CDR 3. Conclusion: Functional dependence for basic activities of daily living becomes more frequent in the most advanced stages of AD, whereas dependence for IADLs is onset since early stages of AD, even more noticeable than dependence for basic ADLs, what suggests a progressive loss of functionality

Aged Lewis rats exposed to low and moderate doses of rotenone are a good model for studying the process of protein aggregation and its effects upon central nervous system cell physiology / Ratos Lewis idosos expostos a baixa e moderada doses de rotenona são um bom modelo para estudar o processo de agregação proteica e seus efeitos sobre a fisiologia celular do sistema nervoso central

ABSTRACT Cell physiology is impaired before protein aggregation and this may be more relevant than inclusions themselves for neurodegeneration. The present study aimed to characterize an animal model to enable the analysis of the cell biology before and after protein aggregation. Ten-month-old Lewis rats were exposed either to 1 or 2 mg/kg/day of rotenone, delivered subcutaneously through mini-pumps, for one month. Hyperphosphorylated TAU, alpha-synuclein, amyloid-beta peptide and protein carbonylation (indicative of oxidative stress) were evaluated in the hippocampus, substantia nigra and locus coeruleus through immunohistochemistry or western blot. It was found that 2 mg/kg/day rotenone increased amyloid-beta peptide, hyperphosphorylation of TAU and alpha-synuclein. Rotenone at 1mg/kg/day did not alter protein levels. Protein carbonylation remained unchanged. This study demonstrated that aged Lewis rats exposed to a low dose of rotenone is a useful model to study cellular processes before protein aggregation, while the higher dose makes a good model to study the effects of protein inclusions.

RESUMO A fisiologia celular está prejudicada antes da agregação proteica podendo ser mais importante para a neurodegeneração do que as próprias inclusões. Assim, o objetivo deste estudo é caracterizar um modelo animal para analisar os mecanismos e efeitos da agregação proteica. Ratos Lewis com 10 meses de idade foram expostos a rotenona (1 ou 2 mg/kg/dia), administrada subcutaneamente, utilizando minibombas osmóticas. Os níveis de peptídeo beta-amiloide, TAU hiperfosforilada, alfa-sinucleína e proteínas carboniladas (indicativo de estresse oxidativo) foram avaliados por imunohistoquímica e western blot no hipocampo, substância negra e locus coeruleus. Foi demonstrado que 2 mg/kg/dia de rotenona promoveu aumento do peptídeo beta-amiloide, hiperfosforilação da TAU e alfa-sinucleína. Já 1 mg/kg/dia de rotenona não alterou os níveis dessas proteína nessas regiões. As proteínas carboniladas não se alteraram. Foi demonstrado que ratos Lewis idosos expostos a baixas doses de rotenona são modelo de estudo dos processos celulares antes da agregação proteica, enquanto 2 mg/kg/dia de rotenona permite estudos sobre os efeitos da agregação proteica.

Gerenciamento do cuidado de enfermagem ao idoso com Alzheimer / Gerenciamiento del cuidado de enfermería al anciano con Alzheimer / Management of nursing care for the elderly with Alzheimer

Introdução: a doença de Alzheimer é a demência mais prevalente na prática clínica da enfermagem. Esta patologia caracteriza-se pela presença de placas amielóides e emaranhados neurofibrilares no cérebro, bem como diminuição geral do cérebro e do número de neurônios. Objetivo: elencar a produção da literatura nacional dos enfermeiros brasileiros sobre o cuidado aos idosos com doença de Alzheimer no período de 2000 a 2011. Métodos: revisão integrativa da literatura, seguindo os pressupostos de Cooper. Foram utilizados os descritores: idoso sendo refinado com o descritor doença de Alzheimer. A busca teve o espaço temporal especificado entre os anos 2000 a 2011. Foram incluídas publicações científicas brasileiras, indexadas na base de dados Literatura Latino Americana do Caribe em Ciências da Saúde, Banco de Dados de Enfermagem e, na Literatura Internacional em Ciências da Saúde que apresentassem o resumo disponível on-line; no idioma português. Conclusão: percebe-se que a maioria das publicações referem-se aos cuidadores e a saúde destes, o que sugere a necessidade de novas pesquisas que visem a construção de plano de cuidados aos idosos com Alzheimer(AU)

Introducción: la enfermedad de Alzheimer es la demencia más frecuente en la práctica clínica de enfermería. Esta patología se caracteriza por la presencia de amielóides placas y ovillos neurofibrilares en el cerebro, y el cerebro y disminución general en el número de neuronas. Objetivo: distinguir la producción de literatura nacional de enfermería sobre el cuidado a ancianos con enfermedad de Alzheimer en el período de 2000 a 2011. Métodos: revisión integrativa de literatura, ciñéndose a los presupuestos de Cooper. Fue utilizado el descriptor Anciano, refinándose la búsqueda con el descriptor enfermedad de Alzheimer. La búsqueda se efectuó de acuerdo al periodo precitado. Fueron incluidas publicaciones científicas brasileñas, indexadas en la base de datos Literatura Latinoamericana y del Caribe en Ciencias de Salud, Banco de Datos de Enfermería y Literatura Internacional en Ciencias de Salud, que presentaran resumen disponible online en lengua portuguesa. Conclusión: se percibe que la mayoría de las publicaciones se refieren a los cuidadores y a su salud, lo cual sugiere la necesidad de nuevas investigaciones apuntando a construir un plan de cuidado a los ancianos con Alzheimer(AU)

Introduction: Alzheimer's disease is the most prevalent dementia in clinical nursing practice. This pathology is characterized by the presence of amielóides plaques and neurofibrillary tangles in the brain, and the brain and general decrease in the number of neurons. Objective: to list the national literature output by Brazilian nurses regarding the care to elderly patients with Alzheimer disease, in the period spanning from 2000 to 2011. Method: integrative literature review, according to Cooper's premises. The following descriptors were used: elderly, refine with the descriptor Alzheimer disease. The search was limited to the period between the years 2000 and 2011. The included articles were Brazilian scientific publications, indexed on the Latin American and Caribbean Health Sciences Database, Nursing Database and the International Health Sciences Literature of which the abstract was available online and in Portuguese. Conclusion: it is observed that most publications refer to care givers and their health, which implies a need for further studies that aim at creating a care plan for the elderly with Alzheimer(AU)