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1.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500640

RESUMO

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 µM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Trombina/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Bovinos , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Relação Estrutura-Atividade
2.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3052-3057, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467695

RESUMO

To study the material basis and mechanism of volatile oil from Alpinia oxyphylla in treating Alzheimer's disease(AD) based on GC-MS and network pharmacology. Ingredients of volatile oil from A.oxyphylla were analyzed by GC-MS. Targets of those ingredients were obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Relevant targets of AD were obtained through such databases as DrugBank, STITCH, OMIM. Intersection targets of ingredients and diseases were obtained by Online Venny map, and PPI network was established by STRING to screen out core targets. Gene ontology(GO) functional enrichment analysis and KEGG pathway enrichment analysis were performed by DAVID. The "ingredients-target-pathway" network was constructed by software Cytoscape 3.8.1 to screen out potential active ingredients of volatile oil from A.oxyphylla in the treatment of AD. The results showed that a total of 6 active ingredients were screened from the volatile oil of A.oxyphylla by GC-MS, 17 targets corresponding to 6 active ingredients were found in TCMSP database, and 3 448 AD targets were found in DrugBank database. "Ingredients-target-pathway" network and PPI network showed there were 4 potential active ingredients in the treatment of AD and 4 core targets. GO analysis and KEGG analysis showed 34(P<0.05) and 5(P<0.05) pathways, respectively, including nerve ligand receptor interaction, calcium signaling pathway, cholinergic synapse and 5-hydroxytryptaminergic synapse. This suggested that volatile oil from A.oxyphylla could synergistically treat AD by regulating calcium balance, cholinergic balance and phosphorylation. This study provided reference and guidance for further study of volatile oil from A.oxyphylla in the treatment of AD.


Assuntos
Alpinia , Doença de Alzheimer , Medicamentos de Ervas Chinesas , Óleos Voláteis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Simulação de Acoplamento Molecular
3.
Alzheimers Res Ther ; 13(1): 147, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479635

RESUMO

BACKGROUND: Leukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time. METHODS: This longitudinal observational study used data from the National Alzheimer's Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models. RESULTS: In AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = -0.200 [-0.380, -0.019] points/year, n = 800) and AD dementia (B = -0.321 [-0.597, -0.046] points/year, n = 604) as measured by CDR Sum of Boxes. CONCLUSIONS: The use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Cognição , Disfunção Cognitiva/tratamento farmacológico , Progressão da Doença , Humanos , Antagonistas de Leucotrienos , Estudos Longitudinais , Testes Neuropsicológicos
4.
J Enzyme Inhib Med Chem ; 36(1): 1860-1873, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34425715

RESUMO

To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 µM for eqBChE, 3.62 µM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; -OCH3 > -CH3 > -Cl (-Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aß1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aß1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Fármacos Neuroprotetores/química , Ácidos Sulfínicos/química , Alcinos/química , Amiloide/metabolismo , Animais , Comportamento Animal , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Humanos , Fígado , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Estrutura Molecular , Teste do Labirinto Aquático de Morris , Sistema Nervoso , Fármacos Neuroprotetores/farmacologia , Relação Estrutura-Atividade , Ácidos Sulfínicos/farmacologia
5.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(3): 240-246, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34374234

RESUMO

Objective: To investigate the effects of novel BimunoGalactooligosaccharides (B-GOS) on cognitive behavior and depression of APP/PS1/tau Alzheimer's disease transgenic mice. Methods: Five-month-old male APP/PS1/tau AD transgenic mice and C57BL/6J control mice were divide into C57+Vehicle group, C57+B-GOS group, APP/PS1/tau+Vehicle group and APP/PS1/tau+B-GOS group, with 10 mice in each group. After continuous administration of B-GOS for 5 months, the cognitive behavior and depressive mood changes of mice in each group were detected by open field experiment, new object recognition experiment, Y maze experiment, Morris water maze experiment, tail suspension test, forced swimming test and conditioned fear experiment, respectively. Results: ①Open field experiment: the percentage of activity time in the central area of open field in APP/PS1/tau+Vehicle group mice was significantly lower than that in C57+Vehicle group mice (P<0.01), and was remarkably increased after B-GOS intervention (P<0.05). ② New object recognition experiment: the new object recognition index (NOI) of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P<0.01), and was observably increased after B-GOS intervention (P<0.05). ③ Y maze experiment: the spontaneous alternation correct rate of APP/PS1/tau+Vehicle group mice was notably lower than that in C57+Vehicle group (P<0.01), and was distinctly increased after B-GOS intervention (P<0.01). ④ Classical water maze experiment: the escape latency of APP/PS1/tau+Vehicle group mice on the 4th and 5th days was significantly longer than that of C57+Vehicle group mice (P<0.01), which was markedly shortened after B-GOS intervention (P<0.05). During the space exploration phase, the percentage of swimming time in the target quadrant and the times of crossing the platform in APP/PS1/tau+Vehicle group mice were significantly lower than those in C57+Vehicle group mice (P<0.01), which were notably increased after B-GOS intervention (P<0.01). ⑤ Tail suspension test and forced swimming test: the percentage of immobility time in APP/PS1/tau+Vehicle group mice was dramatically higher than that in C57+Vehicle group mice (P<0.01), and was obviously reduced after B-GOS intervention (P< 0.01). ⑥ Conditioned fear experiment: before conditioned stimulus (CS), the freezing ratio of mice in each group had no statistical difference (P>0.05). After CS, the freezing ratio of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P<0.01), and was notably increased after B-GOS intervention (P<0.01). Conclusion: B-GOS could reverse the cognitive behavioral impairment of APP/PS1/tau mice and alleviate their depression to a large extent.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Cognição , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética
8.
J Agric Food Chem ; 69(35): 10163-10173, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34459194

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease. Garlic reportedly has various physiological effects, including a role in protecting against dementia. However, the action mechanisms of garlic on AD are not entirely clear. In this study, we investigated the inhibitory activity of garlic essential oil (GEO) against AD-related enzymes and evaluated the distribution of active substances in GEO to the brain. We found that several sulfur compounds in GEO significantly inhibited AD-related enzymes. Sulfur compounds were detected in the serum and brain 6 h post administration. The ratios of allyl mercaptan (24.0 ± 3.9%) and allyl methyl sulfide (49.8 ± 15.6%) in the brain were significantly higher than those in GEO, while those of dimethyl trisulfide (0.89 ± 34.8%), allyl methyl trisulfide (0.41 ± 19.0%), and diallyl trisulfide (0.43 ± 72.8%) in the brain were significantly lower than those in GEO. Similar results were observed in the serum, suggesting that the organosulfur compounds were converted to allyl mercaptan or allyl methyl sulfide in the body. Although allyl mercaptan and allyl methyl sulfide are not the main components of GEO, they might be key molecules to understand the bioactivities of GEO in the body.


Assuntos
Compostos Alílicos , Doença de Alzheimer , Alho , Doenças Neurodegenerativas , Óleos Voláteis , Doença de Alzheimer/tratamento farmacológico , Animais , Encéfalo , Camundongos , Sulfetos , Compostos de Enxofre
10.
Adv Exp Med Biol ; 1331: 31-48, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453291

RESUMO

Recent research has demonstrated that degeneration of the basal forebrain cholinergic system, far from being a mere downstream mediator of Alzheimer's disease (AD) symptoms, may play a disease-aggravating role in the continuum of AD pathology. The search for novel biomarkers of the cholinergic deficit in AD and novel therapeutic targets for the sustenance of the basal forebrain cholinergic system has therefore taken on more urgency. A novel model that explains the preferential vulnerability of basal forebrain cholinergic neurons in AD as the result of pathological alterations to nerve growth factor (NGF) metabolism offers an integrated investigative platform for the development of such biomarkers and therapeutics. By positing a reciprocal trophic interaction between the basal forebrain and its target tissues, this model can also explain the disease-modifying nature of the cholinergic deficit in AD and can incorporate other key factors in basal forebrain cholinergic degeneration, including NGF receptor changes and retrograde transport deficits in AD. This chapter will focus on the potential of NGF metabolic pathway biomarkers in AD as well as therapeutic targets to correct NGF metabolic deficits, aiding the development of novel pro-cholinergic therapeutics.


Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Doença de Alzheimer/tratamento farmacológico , Biomarcadores , Humanos , Redes e Vias Metabólicas , Fator de Crescimento Neural/metabolismo
11.
Adv Exp Med Biol ; 1331: 193-202, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453299

RESUMO

Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain characterized by extracellular beta-amyloid plaques, intraneuronal tau inclusions, vascular impairment, inflammation, neurodegeneration, and memory loss. Acetylcholine is the most important neurotransmitter for memory, and cholinergic neurons selectively degenerate in AD, and a loss of acetylcholine directly correlates with cognitive decline. Nerve growth factor (NGF) is the most potent growth factor to support the survival of these cholinergic neurons. Thus, researchers are interested to deliver NGF directly into the brain to the cholinergic neurons. As the brain is isolated by the blood-brain barrier, the large protein NGF cannot easily pass into the brain, and peripheral administration of NGF also causes severe side effects. Blood cells may represent a potent therapeutic strategy to deliver NGF into the brain. Monocytes can be isolated and loaded with NGF and may transmigrate into the brain. As monocytes are precursors of microglia, they may differentiate and release NGF but also phagocyte and eliminate toxic plaques. Platelets are small anuclear cells and become rapidly activated during vascular lesions, and they may migrate to lesion sites and repair blood vessels and also eliminate toxic beta-amyloid depositions in vessels. In order to guarantee a stable and slow release, the use of biomaterials is of interest, especially collagen hydrogels that may be useful to protect these transmigrating blood cells. In this review, I summarize advantages and challenges of using transmigrating cells to deliver NGF directly into the brain.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Colágeno , Humanos , Hidrogéis , Monócitos , Fator de Crescimento Neural
12.
Adv Exp Med Biol ; 1331: 167-191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453298

RESUMO

Age-dependent progressive neurodegeneration and associated cognitive dysfunction represent a serious concern worldwide. Currently, dementia accounts for the fifth highest cause of death, among which Alzheimer's disease (AD) represents more than 60% of the cases. AD is associated with progressive cognitive dysfunction which affects daily life of the affected individual and associated family. The cognitive dysfunctions are at least partially due to the degeneration of a specific set of neurons (cholinergic neurons) whose cell bodies are situated in the basal forebrain region (basal forebrain cholinergic neurons, BFCNs) but innervate wide areas of the brain. It has been explicitly shown that the delivery of the neurotrophic protein nerve growth factor (NGF) can rescue BFCNs and restore cognitive dysfunction, making NGF interesting as a potential therapeutic substance for AD. Unfortunately, NGF cannot pass through the blood-brain barrier (BBB) and thus peripheral administration of NGF protein is not viable therapeutically. NGF must be delivered in a way which will allow its brain penetration and availability to the BFCNs to modulate BFCN activity and viability. Over the past few decades, various methodologies have been developed to deliver NGF to the brain tissue. In this chapter, NGF delivery methods are discussed in the context of AD.


Assuntos
Doença de Alzheimer , Prosencéfalo Basal , Doença de Alzheimer/tratamento farmacológico , Humanos , Fator de Crescimento Neural/metabolismo , Neurônios/metabolismo
13.
ACS Chem Neurosci ; 12(18): 3467-3476, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34463471

RESUMO

Aggregation of amyloid ß42 (Aß42) is one of the hallmarks of Alzheimer's disease (AD). The mechanism of Aß42 aggregation mainly consists of two phases, nucleation and elongation (including plateau region as a saturation phase). During the nucleation phase, the monomer gradually forms toxic oligomers. During the elongation phase, each nucleus acts as a template and associates with monomers to initiate less toxic fibrillization. We previously proposed a method of classifying compounds into nine groups based on their ability to modulate the nucleation and/or elongation phases. An orcein derivative (O4), which is a phenoxazine dye isolated from the lichen Roccella tinctoria and containing a 2,5-cyclohexadienone moiety, was reported to convert oligomers into relatively inert fibrils, resulting in the reduction of the neurotoxicity of Aß42. Focusing on O4 in the pursuit of anti-AD drugs, we herein screened 480 natural products including NPDepo (RIKEN) for the compounds that delayed the nucleation phase and promoted the elongation phase. The signal intensities for Aß42 treated with each of the 15 compounds that met these criteria were lowered in dot blotting using antioligomer antibody, and the fibril formation of Aß42 in the presence of these compounds was observed in transmission electron microscopy. Among the 15 compounds, 12 compounds (80%) reduced the toxicity of Aß42 against mouse neuroblastoma Neuro-2a cells. Some of these anticytotoxic compounds contain 2-pyrone and 4-pyrone that interacted with Aß42, maybe by shifting the equilibrium of Aß from toxic oligomer into inert fibrils.


Assuntos
Doença de Alzheimer , Produtos Biológicos , Doença de Alzheimer/tratamento farmacológico , Amiloide , Peptídeos beta-Amiloides , Animais , Ascomicetos , Camundongos , Fragmentos de Peptídeos
14.
Biomolecules ; 11(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356628

RESUMO

Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. Various pathogenic mechanisms have been proposed to contribute to disease progression, and recent research provided evidence linking dysregulated circadian rhythms/sleep and energy metabolism with AD. Previously, we found that the natural compound Nobiletin (NOB) can directly activate circadian cellular oscillators to promote metabolic health in disease models and healthy aging in naturally aged mice. In the current study, using the amyloid-ß AD model APP/PS1, we investigated circadian, metabolic and amyloid characteristics of female mice and the effects of NOB. Female APP/PS1 mice showed reduced sleep bout duration, and NOB treatment exhibited a trend to improve it. While glucose tolerance was unchanged, female APP/PS1 mice displayed exaggerated oxygen consumption and CO2 production, which was mitigated by NOB. Likewise, cold tolerance in APP/PS1 was impaired relative to WT, and interestingly was markedly enhanced in NOB-treated APP/PS1 mice. Although circadian behavioral rhythms were largely unchanged, real-time qPCR analysis revealed altered expression of several core clock genes by NOB in the cerebral cortex, notably Bmal1, Npas2, and Rora. Moreover, NOB was also able to activate various clock-controlled metabolic genes involved in insulin signaling and mitochondrial function, including Igf1, Glut1, Insr, Irs1, Ucp2, and Ucp4. Finally, we observed that NOB attenuated the expression of several AD related genes including App, Bace1, and ApoE, reduced APP protein levels, and strongly ameliorated Aß pathology in the cortex. Collectively, these results reveal novel genotype differences and importantly beneficial effects of a natural clock-enhancing compound in biological rhythms and related pathophysiology, suggesting the circadian clock as a modifiable target for AD.


Assuntos
Doença de Alzheimer , Ritmo Circadiano/efeitos dos fármacos , Flavonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Ritmo Circadiano/genética , Modelos Animais de Doenças , Feminino , Camundongos
15.
Biomaterials ; 276: 121065, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34391018

RESUMO

Clearance of peripheral amyloid-ß (Aß) has been demonstrated particularly promising for overcoming the blood-brain barrier (BBB) hurdle to remove brain-derived Aß associated with Alzheimer's disease (AD). However, currently used therapeutic agents targeting peripheral Aß cannot simultaneously achieve plasma Aß enrichment and enhanced clearance, which may result in poor bioavailability and rather low efficacy. Moreover, most of therapeutic agents usually promote the unfavorable aggregation of Aß. Herein, we construct a near-infrared (NIR) regulated surface-transformable and target peptide-guided upconversion platform (UCNP/ONA-P/K), serving as a safe and effective way for Aß clearance. Taking advantage of extended blood circulation, high selectivity toward Aß, and surface-transformable property, such UCNP/ONA-P/K can address the challenges of peripheral Aß clearance by a combination of enhancing the enrichment of plasma Aß, preventing the unfavorable aggregation of Aß and simultaneously facilitating the hepatic clearance of the captured Aß. After verified by a series of systematic toxicity evaluation, cell uptake, deep tissue penetration, and hemolytic experiments, in vivo studies demonstrate that UCNP/ONA-P/K can efficiently decrease brain Aß burden and reverse memory deficits in 3xTg-AD mice. Overall, this NIR multi-functional design provides a new biocompatible and efficient way for Aß removal, which will promote the application of peripheral clearance of Aß for AD treatment.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Camundongos
17.
Artigo em Inglês | MEDLINE | ID: mdl-34444325

RESUMO

We investigated the preventive and risk factors of rapid cognitive decline in patients with Alzheimer's disease (AD). Using the Chang Gung Research Database (CGRD), we enrolled patients with AD aged over 65 years between 1 January 2001 and 30 May 2019, and followed up for at least two years. Rapid cognitive decline was defined by a Mini-Mental State Examination (MMSE) score decline of ≥4 in 2 years. A longer prescription of acetylcholinesterase inhibitors (AChEIs) was defined as 22 months based on the median treatment duration of the cohorts. The Cox proportional hazards regression model adjusted for age, sex, medication, and physical comorbidities was used to examine the candidate risk and protective factors. We analyzed data from 3846 patients with AD (1503 men, 2343 women) with a mean age and percentage of females of 77.8 ± 6.2 years and 60.9%, respectively. The mean duration of patients with AD receiving AChEIs was 658.7 ± 21.9 days. In general, 310 patients with AD showed a rapid cognitive decline, accounting for 8.1%. Treatment of a consecutive AChEI prescription for >22 months in patients with AD was a protective factor against rapid cognitive decline (adjusted hazard ratio (aHR) = 0.41, 95% confidence interval (CI) = 0.33-0.52, p < 0.001). Patients with AD aged >85 years (aHR = 0.53, 95% CI = 0.36-0.79, p < 0.01) and aged 75-85 years (aHR = 0.73, 95% CI = 0.57-0.93, p < 0.05) had a significantly lower risk of rapid cognitive decline than those aged 65-75 years. Additionally, patients with mild and moderate AD (clinical dementia rating (CDR = 1, aHR = 1.61, 95% CI = 1.26-2.07, p < 0.001; CDR = 2, aHR = 2.64, 95% CI = 1.90-3.65, p < 0.001) were more likely to have rapid cognitive decline than those with early AD (CDR = 0.5). Sex, medication with different types of AChEIs, and physical comorbidities were not associated with rapid cognitive decline. These findings indicate that it is important to maintain longer consecutive AChEI prescriptions in patients with AD to prevent cognitive decline.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Testes de Estado Mental e Demência
18.
Free Radic Biol Med ; 174: 281-304, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352370

RESUMO

Cognitive decline, decrease in neuronal function and neuronal loss that accompany normal aging and dementia are the result of multiple mechanisms, many of which involve oxidative stress. Herein, we review these various mechanisms and identify pharmacological and non-pharmacological approaches, including modification of diet, that may reduce the risk and progression of cognitive decline. The optimal degree of neuronal protection is derived by combinations of, rather than individual, compounds. Compounds that provide antioxidant protection are particularly effective at delaying or improving cognitive performance in the early stages of Mild Cognitive Impairment and Alzheimer's disease. Laboratory studies confirm alleviation of oxidative damage in brain tissue. Lifestyle modifications show a degree of efficacy and may augment pharmacological approaches. Unfortunately, oxidative damage and resultant accumulation of biomarkers of neuronal damage can precede cognitive decline by years to decades. This underscores the importance of optimization of dietary enrichment, antioxidant supplementation and other lifestyle modifications during aging even for individuals who are cognitively intact.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/tratamento farmacológico , Cognição , Disfunção Cognitiva/tratamento farmacológico , Suplementos Nutricionais , Humanos , Laboratórios
19.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360966

RESUMO

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas/métodos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Medicina de Precisão/métodos
20.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360973

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estimulação Magnética Transcraniana/métodos , Doença de Alzheimer/terapia , Animais , Humanos , Medicina de Precisão/métodos
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