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1.
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
2.
Medicine (Baltimore) ; 100(35): e27055, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477136

RESUMO

ABSTRACT: This study aimed to assess the longitudinal changes in amyloid beta (Aß) deposition in cortical regions with [11C]-PIB PET in initially amyloid-negative non-demented subjects and evaluate whether amyloid-negative subjects convert to amyloid-positive.Sixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (aged 60-75 years), who were amyloid-negative at baseline, underwent 60-minute dynamic [11C]-PIB PET and cognitive assessment over 5.0 to 9.4 years of a long follow-up, and the apolipoprotein-E (APOE) genotype was assessed. Regions of interest were defined in the bilateral cortex on coregistered MRI. Quantitative analysis of [11C]-PIB was performed using the distribution value ratio (DVR). Longitudinal changes in global and regional PIB DVRs were evaluated in the same regions, and the annual rate of change in the PIB DVR was calculated.Seven (30.4%) of 23 initially amyloid-negative non-demented subjects converted to globally amyloid-positive (global PIB DVR ≥1.40) over a follow-up of 6.5 ±â€Š1.4 years (converter). The global PIB DVR in converters increased from 1.22 ±â€Š0.07 at baseline to 1.63 ±â€Š0.15 (n = 7, P < .01) at last follow-up, and an annual increase of global PIB DVR was 0.057 ±â€Š0.019/year (n = 7, P < .01). In contrast, the global PIB DVR in the remaining 16 subjects was 1.15 ±â€Š0.07 at baseline and did not change over a follow-up period (stable). The APOE ε4 allele was present in 4 (57.1%) of the 7 converters, differing from 2 (12.5%) of 16 stable subjects (Fisher's exact test, P < .05). Three amyloid-negative MCI subjects had an annual increase in global PIB DVR above 0.061/year and became positive at 2.8 ±â€Š0.5 years of follow-up, which was faster than 5.0 ±â€Š2.0 years in 4 CN subjects. The regional PIB DVR that increased early above the regional positivity threshold was most frequently found in the right lateral temporal cortex (71.4%), followed by the left frontal cortex (41.8%).Our results suggest that the initially amyloid-negative CN and MCI subjects, especially with APOE ε4, can become globally amyloid-positive over a longer time, based on early regional Aß deposition in the lateral temporal cortex and/or frontal cortex.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/análise , Placa Amiloide/complicações , Idoso , Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Amiloide/fisiopatologia , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/estatística & dados numéricos
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.
Alzheimers Res Ther ; 13(1): 148, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479648

RESUMO

BACKGROUND: Thoroughly understanding the temporal associations between cognitive and functional dimensions along the dementia process is fundamental to define preventive measures likely to delay the disease's onset. This work aimed to finely describe the trajectories of cognitive and functional declines, and assess their dynamic bidirectional relationships among subjects at different stages of the dementia process. METHODS: We leveraged extensive repeated data of cognition and functional dependency from the French prospective COGICARE study, designed to better characterize the natural history of cognitive and functional declines around dementia diagnosis. Cognition was measured by the Mini-Mental State Examination, the Isaacs Set Test for verbal fluency, the Benton Visual Retention Test for visuo-spatial memory, and Trail Making Test Part B for executive functioning. Functional dependency was measured by basic and instrumental activities of daily living. The study included 102 cognitively normal, 123 mildly cognitively impaired, and 72 dementia cases with a median of 5 repeated visits over up to 57 months. We used a dynamic causal model which addresses the two essential issues in temporal associations assessment: focusing on intra-individual change and accounting for time. RESULTS: Better cognitive abilities were associated with lower subsequent decline of the functional level among the three clinical stages with an intensification over time but no reciprocity of the association whatever the clinical status. CONCLUSION: This work confirms that the progressive functional dependency could be induced by cognitive impairment. Subjects identified as early as possible with clinically significant cognitive impairments could benefit from preventive measures before the deterioration of activities of daily living and the appearance of dementia clinical signs.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Atividades Cotidianas , Cognição , Humanos , Testes Neuropsicológicos , Estudos Prospectivos
5.
Alzheimers Res Ther ; 13(1): 149, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488866

RESUMO

BACKGROUND: Alzheimer's disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer's disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of ~150 individuals with Alzheimer's disease and ~135 healthy controls, to investigate this knowledge gap. METHODS: Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer's disease. Alzheimer's disease predictive models were constructed using machine learning combined with stepwise logistic regression. RESULTS: In both plasma and cerebrospinal fluid, individuals with Alzheimer's disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer's disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively. CONCLUSIONS: Previous studies report Alzheimer's disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer's disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Epóxido Hidrolases , Sistema Enzimático do Citocromo P-450 , Ácidos Graxos , Humanos , Oxilipinas
6.
Alzheimers Res Ther ; 13(1): 150, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488875

RESUMO

BACKGROUND: Aging is associated with declining protective immunity and persistent low-grade inflammatory responses, which significantly contribute to Alzheimer's disease (AD) pathogenesis. Detecting aging-related cerebral vulnerability associated with deterioration of the immune system requires from non-invasive biomarkers able to detect failures in the brain-immunity connection. Reduced levels of salivary lactoferrin (sLF), an iron-binding protein with immunomodulatory activity, have been related to AD diagnosis. However, it remains unknown whether decreased sLF is associated with increased cortical amyloid-beta (Aß) load and/or with loss of cortical integrity in normal aging. METHODS: Seventy-four cognitively normal older adults (51 females) participated in the study. We applied multiple linear regression analyses to assess (i) whether sLF is associated with cortical Aß load measured by 18F-Florbetaben (FBB)-positron emission tomography (PET), (ii) whether sLF-related variations in cortical thickness and cortical glucose metabolism depend on global Aß burden, and (iii) whether such sLF-related cortical abnormalities moderate the relationship between sLF and cognition. RESULTS: sLF was negatively associated with Aß load in parieto-temporal regions. Moreover, sLF was related to thickening of the middle temporal cortex, increased FDG uptake in the posterior cingulate cortex, and poorer memory. These associations were stronger in individuals showing the highest Aß burden. CONCLUSIONS: sLF levels are sensitive to variations in cortical Aß load, structural and metabolic cortical abnormalities, and subclinical memory impairment in asymptomatic older adults. These findings provide support for the use of sLF as a non-invasive biomarker of cerebral vulnerability in the general aging population.


Assuntos
Doença de Alzheimer , Lactoferrina , Idoso , Envelhecimento , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Feminino , Humanos , Tomografia por Emissão de Pósitrons
7.
Alzheimers Res Ther ; 13(1): 151, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488882

RESUMO

BACKGROUND: In Alzheimer's disease, amyloid- ß (A ß) peptides aggregate in the lowering CSF amyloid levels - a key pathological hallmark of the disease. However, lowered CSF amyloid levels may also be present in cognitively unimpaired elderly individuals. Therefore, it is of great value to explain the variance in disease progression among patients with A ß pathology. METHODS: A cohort of n=2293 participants, of whom n=749 were A ß positive, was selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to study heterogeneity in disease progression for individuals with A ß pathology. The analysis used baseline clinical variables including demographics, genetic markers, and neuropsychological data to predict how the cognitive ability and AD diagnosis of subjects progressed using statistical models and machine learning. Due to the relatively low prevalence of A ß pathology, models fit only to A ß-positive subjects were compared to models fit to an extended cohort including subjects without established A ß pathology, adjusting for covariate differences between the cohorts. RESULTS: A ß pathology status was determined based on the A ß42/A ß40 ratio. The best predictive model of change in cognitive test scores for A ß-positive subjects at the 2-year follow-up achieved an R2 score of 0.388 while the best model predicting adverse changes in diagnosis achieved a weighted F1 score of 0.791. A ß-positive subjects declined faster on average than those without A ß pathology, but the specific level of CSF A ß was not predictive of progression rate. When predicting cognitive score change 4 years after baseline, the best model achieved an R2 score of 0.325 and it was found that fitting models to the extended cohort improved performance. Moreover, using all clinical variables outperformed the best model based only on a suite of cognitive test scores which achieved an R2 score of 0.228. CONCLUSION: Our analysis shows that CSF levels of A ß are not strong predictors of the rate of cognitive decline in A ß-positive subjects when adjusting for other variables. Baseline assessments of cognitive function accounts for the majority of variance explained in the prediction of 2-year decline but is insufficient for achieving optimal results in longer-term predictions. Predicting changes both in cognitive test scores and in diagnosis provides multiple perspectives of the progression of potential AD subjects.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides , Biomarcadores , Cognição , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Humanos , Testes Neuropsicológicos , Proteínas tau
8.
Zhen Ci Yan Jiu ; 46(8): 635-41, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472747

RESUMO

OBJECTIVE: To observe the effect of Sanjiao acupuncture(triple energizer acupuncture)on the small G protein guanosine triphosphate enzyme subfamily protein RhoA/Rho kinase (ROCK) pathway in Alzheimer's disease mice, and explore its effect on learning and memory function and neurosynaptic plasticity. METHODS: Forty SAMP8 senile dementia mice were randomly divided into model, Sanjiao acupuncture (acupuncture), non acupoint acupuncture (non-acupoint) and fasudil groups, with 10 mice in each group, another 10 SAMR normal aging mice were selected as normal aging group. Mice in the acupuncture group were treated with acupuncture intervention on "Danzhong"(CV18), "Zhongwan"(CV13), "Qihai"(BL24) and bilateral "Xuehai"(SP10) and "Zusanli" (ST36). Mice in the non-acupoint group were treated with acupuncture at each of the left and right non-acupoints under the ribs and mice in the fasudil group were intraperitoneally injected with fasudil (25 mg/kg). The mice in each group were given medicine or acupuncture on the second day after grouping for 28 continuously days, once a day. Morris water maze test was used to test the learning and memory ability of mice. HE staining was used to observe the pathological changes of neurons in hippocampus. The number of hippocampal neuron dendritic spine was detected by FD fast Golgi staining kit. The contents of ß-amyloid 42 (Aß42) and phosphorylated tau protein (p-tau) in hippocampus were detected by ELISA. Western blot was used to detect the protein relative expression levels of RhoA, ROCK, F-actin and p-cofilin in hippocampus. RESULTS: Compared with those in the normal aging group, the hippocampal neurons of the model group were disorderly arranged, the number of neuron was reduced, the escape latency, hippocampal Aß42 and p-tau contents, RhoA and ROCK protein expressions increased (P<0.05), the number of crossing the original platform, the number of neuronal dendritic spines, expressions of F-actin and p-cofilin decreased (P<0.05). After the interventions, there was no statistically significant difference in the above indicators in the non-acupoint group relevant to the model group (P>0.05). The acupuncture group and fasudil group improved the hippocampal pathological damage. The escape latency, hippocampal Aß42 and p-tau contents, the expressions of RhoA and ROCK protein decreased (P<0.05), and the number of crossing the original platform, the number of hippocampal neuron dendritic spines, expressions of F-actin and p-cofilin increased (P<0.05) in both of the acupuncture and fasudil groups in contrast to the model and non-acupoint groups. Compared with the acupuncture group, there was no significant difference in the above indicators in the fasudil group (P>0.05). CONCLUSION: Sanjiao acupuncture may inhibit the activation of the RhoA/ROCK pathway, so as to improve the learning and memory function of AD mice, increase the number of hippocampal neuron dendritic spines, and promote synaptic plasticity.


Assuntos
Terapia por Acupuntura , Doença de Alzheimer , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Aprendizagem , Camundongos , Plasticidade Neuronal , Quinases Associadas a rho/genética
9.
Cad Saude Publica ; 37(8): e00073320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495090

RESUMO

Brazil has the second highest age-standardized prevalence of Alzheimer's disease worldwide. However, information about Alzheimer's disease-related hospitalizations in Brazil is scarce despite its economic and social impact. We described temporal trends in hospitalizations related to Alzheimer's disease in Brazil from 2010 to 2019. We conducted a time-series, retrospective, descriptive, national-based study using data from the DATASUS database of the Brazilian Ministry of Health. Hospitalizations, mean days hospitalized, and economic costs from those hospitalizations were extracted from 2010 to 2019. Hospitalizations by Alzheimer's disease increased 87.7% from 2010 to 2019, with greater increase among men (97.4%), mixed ethnicity (224%), 80 years or older (115.1%), and in the Northeast (172.1%) and Central West (144.2%) regions. Although mean days hospitalized decreased in all subgroups, an increasing time trend in hospital admission was observed in the Central West Region. Costs per hospitalization increased for patients aged 50 years or younger and in admissions related to emergency services. Compared with other non-communicable chronic diseases, Alzheimer's disease had the highest increase in absolute number and rate of hospitalizations in Brazil from 2010 to 2019. AD is a public health problem in Brazil. Strategies to reduce its burden are necessary but only if accompanied by greater equality and awareness of this disease.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/epidemiologia , Brasil/epidemiologia , Custos e Análise de Custo , Hospitalização , Humanos , Masculino , Estudos Retrospectivos
10.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(4): 628-633, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34494536

RESUMO

Neurodegenerative diseases are associated with neuroinflammation,oxidative stress,and aging,which can lead to cognitive and motor dysfunctions.Recent studies suggest that the development of neurodegenerative diseases is related to adaptive immunity,in which CD4+T cells are involved as adaptive immune cells.Through different pathways,CD4+T cells differentiate into effector and regulatory subsets,which may have different effects on the progression of neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease,multiple sclerosis,and amyotrophic lateral sclerosis.Here,we review the role and research progress of CD4+T cells in neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Esclerose Amiotrófica Lateral , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Linfócitos T
11.
Trials ; 22(1): 508, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34332638

RESUMO

BACKGROUND: Although Alzheimer's disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer's disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer's disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer's disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer's disease. METHODS: The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer's disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values. DISCUSSION: This is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer's disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03489044 . Registered on April 5, 2018.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Animais , Estudos Cross-Over , Método Duplo-Cego , Humanos , Levetiracetam/efeitos adversos , Camundongos , Estudo de Prova de Conceito , Qualidade de Vida
13.
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
14.
Adv Exp Med Biol ; 1331: 145-165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453297

RESUMO

Alzheimer's disease (AD), one of the most common causes of dementia in elderly people, is characterized by progressive impairment in cognitive function, early degeneration of basal forebrain cholinergic neurons (BFCNs), abnormal metabolism of the amyloid precursor protein (APP), amyloid beta-peptide (Aß) depositions, and neurofibrillary tangles. According to the cholinergic hypothesis, dysfunction of acetylcholine-containing neurons in the basal forebrain contributes markedly to the cognitive decline observed in AD. In addition, the neurotrophic factor hypothesis posits that the loss nerve growth factor (NGF) signalling in AD may account for the vulnerability to atrophy of BFCNs and consequent impairment of cholinergic functions. Though acetylcholinesterase inhibitors provide only partial and symptomatic relief to AD patients, emerging data from in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) studies in mild cognitive impairment (MCI) and AD patients highlight the early involvement of BFCNs in MCI and the early phase of AD. These data support the cholinergic and neurotrophic hypotheses of AD and suggest new targets for AD therapy.Different mechanisms account for selective vulnerability of BFCNs to AD pathology, with regard to altered metabolism of APP and tau. In this review, we provide a general overview of the current knowledge of NGF and APP interplay, focusing on the role of APP in regulating NGF receptors trafficking/signalling and on the involvement of NGF in modulating phosphorylation of APP, which in turn controls APP intracellular trafficking and processing. Moreover, we highlight the consequences of APP interaction with p75NTR and TrkA receptor, which share the same binding site within the APP juxta-membrane domain. We underline the importance of insulin dysmetabolism in AD pathology, in the light of our recent data showing that overlapping intracellular signalling pathways stimulated by NGF or insulin can be compensatory. In particular, NGF-based signalling is able to ameliorates deficiencies in insulin signalling in the medial septum of 3×Tg-AD mice. Finally, we present an overview of NGF-regulated microRNAs (miRNAs). These small non-coding RNAs are involved in post-transcriptional regulation of gene expression , and we focus on a subset that are specifically deregulated in AD and thus potentially contribute to its pathology.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Idoso , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animais , Humanos , Camundongos , Fator de Crescimento Neural , Neurônios
15.
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
16.
Pol Merkur Lekarski ; 49(292): 266-268, 2021 Aug 16.
Artigo em Polonês | MEDLINE | ID: mdl-34464365

RESUMO

The consequences of forced isolation due to the risk of SARS-CoV-2 infection in patients with symptoms of dementia in the elderly are only now being analyzed. AIM: The aim of the study was to conduct a preliminary analysis of the effects of a break in implementing rehabilitation programs in patients with Alzheimer's disease with symptoms of dementia. MATERIALS AND METHODS: The analysis included data obtained from qualification tests of 19 patients (14 women, 5 men) aged 76 to 91 years (mean 81.2 +/- 9.9 years) qualified in 2021 to return to groups at the Alzheimer Center in Warsaw. The obtained results of the performed Katz, Lawton tests and the Mini-Mental State Examination (MMSE) were compared with the results from 2020. RESULTS: The initial assessment showed a deterioration of the general and mental condition of patients qualified for the planned activities. The Katz test for the assessment of basic activities of everyday life did not reveal any significant changes in relation to the results obtained one year ago, while the Lawton test for the assessment of complex activities of daily life showed that 13 (68%) of the subjects significantly deteriorated compared to the previous year's study. On the other hand, in the MMSE, deterioration was noted in 12 (63%) analyzed compared to their state from a year ago. CONCLUSIONS: During the year of forced isolation due to the risk of SARS-CoV-2 infection, there was a significant deterioration in the daily activities and cognitive functions of patients with symptoms of dementia in the elderly.


Assuntos
Doença de Alzheimer , COVID-19 , Transtornos Cognitivos , Idoso , Cognição , Feminino , Humanos , Masculino , SARS-CoV-2
17.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445342

RESUMO

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Inibidores de Histona Desacetilases/farmacocinética , Histona Desacetilases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Histona Desacetilases/classificação , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Células Tumorais Cultivadas
18.
Artigo em Inglês | MEDLINE | ID: mdl-34360133

RESUMO

Apathy, a common neuropsychiatric symptom associated with dementia, has a strong impact on patients' and caregivers' quality of life. However, it is still poorly understood and hard to define. The main objective of the ECOCAPTURE programme is to define a behavioural signature of apathy using an ecological approach. Within this program, ECOCAPTURE@HOME is an observational study which aims to validate a method based on new technologies for the remote monitoring of apathy in real life. For this study, we plan to recruit 60 couples: 20 patient-caregiver dyads in which patients suffer from behavioral variant Fronto-Temporal Dementia, 20 patient-caregiver dyads in which patients suffer from Alzheimer Disease and 20 healthy control couples. These dyads will be followed for 28 consecutive days via multi-sensor bracelets collecting passive data (acceleration, electrodermal activity, blood volume pulse). Active data will also be collected by questionnaires on a smartphone application. Using a pool of metrics extracted from these passive and active data, we will validate a measurement model for three behavioural markers of apathy (i.e., daytime activity, quality of sleep, and emotional arousal). The final purpose is to facilitate the follow-up and precise diagnosis of apathy, towards a personalised treatment of this condition within everyday life.


Assuntos
Doença de Alzheimer , Apatia , Doença de Alzheimer/diagnóstico , Cuidadores , Humanos , Estudos Observacionais como Assunto , Qualidade de Vida , Inquéritos e Questionários
19.
Artigo em Inglês | MEDLINE | ID: mdl-34360360

RESUMO

BACKGROUND: Music interventions are promising therapies for the management of symptoms in Alzheimer's disease (AD). Globally, music interventions can be classified as active or receptive depending on the participation of the subjects. Active and receptive music tasks engage different brain areas that might result in distinctive clinical effects. This study aims to compare the clinical effects of two types of music interventions and a control activity. METHODS: Ninety AD patients from six nursing homes participated in the study. Nursing homes were randomly and blindly assigned to receive either active music intervention, receptive music intervention, or the usual care. Effects on cognition, behaviour, daily living activities, and motor function were assessed. RESULTS: Active music intervention improved cognition, behaviour, and functional state in a higher extent than both receptive music intervention and usual care. The effect size of active music intervention for cognitive deficits and behavioural symptoms was large (η2 = 0.62 and 0.61, respectively), while for functional state, it was small-to-medium sized (η2 = 0.18). Receptive music intervention had a stabilizing effect on behavioural symptoms compared to control intervention (mean change from baseline ± standard deviation = -0.76 ± 3.66 and 3.35 ± 3.29, respectively). In the active music intervention, the percentage of patients who showed improvement in cognitive deficits (85.7), behavioural symptoms (92.9), and functional state (46.4) was higher than in both receptive listening (11.8, 42.9, and 14.3, respectively) and control group (6.3, 12.2, and 17.1, respectively). CONCLUSIONS: Active music intervention is useful to improve symptoms of AD and should be prescribed as a complement to the usual treatment.


Assuntos
Doença de Alzheimer , Musicoterapia , Música , Atividades Cotidianas , Doença de Alzheimer/terapia , Humanos , Casas de Saúde
20.
Anal Chem ; 93(32): 11337-11345, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34353021

RESUMO

Alzheimer's disease (AD) has become a global threat to the elderly health with a short survival time after diagnosis. Due to the asymptomatic stage during the early development, patients are usually diagnosed at the middle or late stage. Therefore, an efficient tool for AD early diagnosis deserves considerable attention, which could make a significant contribution to the treatment intervention. A fluorescent probe has been widely applied for detecting and visualizing species of interest in vitro and in vivo, and the proper reaction between the probe and analytes is responsible for the fluorescence change to provide a lighting-on or ratiometric responsive pattern with satisfactory sensing behavior. In this work, we report the first attempt to build up an AND-logic probe P2 for AD accuracy diagnosis taking butyrylcholinesterase (BChE) and reactive oxygen species (ROSs) as dual targets. Upon the co-stimulation by these two factors through enzymatic hydrolysis and redox reaction, the NIR emission could be readily turned on. This AND sensing pattern avoided the false-positive response effectively, and other diseases sharing one biomarker could hardly induce a NIR fluorescence response. The sensing assay has also been confirmed to be feasible in vitro and in vivo with good sensibility and selectivity. It is worth mentioning that the probe structure has been optimized in terms of the linkage length. This study shows that probe P2 with a connecting arm of medium length (one methylene, n = 1) has superior sensing performance, promising to provide a reference for the relative structure design.


Assuntos
Doença de Alzheimer , Corantes Fluorescentes , Idoso , Doença de Alzheimer/diagnóstico , Biomarcadores , Butirilcolinesterase , Humanos , Lógica
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