RESUMO
Ferritin, an iron storage and regulation protein, has been associated with Alzheimer's disease (AD); however, it has not been investigated in preclinical AD, detected by neocortical amyloid-ß load (NAL), before cognitive impairment. Cross-sectional analyses were carried out for plasma and serum ferritin in participants in the Kerr Anglican Retirement Village Initiative in Aging Health cohort. Subjects were aged 65-90 years and were categorized into high and low NAL groups via positron emission tomography using a standard uptake value ratio cutoff=1.35. Ferritin was significantly elevated in participants with high NAL compared with those with low NAL, adjusted for covariates age, sex, apolipoprotein E É4 carriage and levels of C-reactive protein (an inflammation marker). Ferritin was also observed to correlate positively with NAL. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve (AUC)=0.766), but was outperformed when plasma ferritin was added to the base model (AUC=0.810), such that at 75% sensitivity, the specificity increased from 62 to 71% on adding ferritin to the base model, indicating that ferritin is a statistically significant additional predictor of NAL over and above the base model. However, ferritin's contribution alone is relatively minor compared with the base model. The current findings suggest that impaired iron mobilization is an early event in AD pathogenesis. Observations from the present study highlight ferritin's potential to contribute to a blood biomarker panel for preclinical AD.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Ferritinas/sangue , Neocórtex/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Neocórtex/diagnóstico por imagem , Tamanho do Órgão , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Sensibilidade e EspecificidadeRESUMO
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. There is no test for its definitive diagnosis in routine clinical practice. Although phase III clinical trials have failed, only symptomatic treatment is currently available; a possible reason for these failed trials is that intervention commenced at an advanced stage of the disease. The hallmarks of an AD brain include plaques comprising of extracellular beta-amyloid (Aß) protein aggregates and intracellular hyperphosphorylated neurofibrillary tangles of tau. Research into the preclinical diagnosis of AD has provided considerable evidence regarding early neuropathological changes using brain Aß imaging and the cerebrospinal fluid biomarkers, Aß and tau. Both these approaches have limitations that are expensive, invasive or time consuming and thus preclude them from screening at-risk population. Recent studies have demonstrated the presence of Aß plaques in the eyes of AD subjects, which is positively associated with their brain Aß burden. Thus ocular biomarkers point to a potential avenue for an earlier, relatively low-cost diagnosis in order for therapeutic interventions to be effective. Here we review the literature that spans the investigation for the presence of Aß in aging eyes and the significance of its deposition in relation to AD pathology. We discuss clinical studies investigating in vivo imaging of Aß in the eye and its association with brain Aß burden and therapies that target ocular Aß. Finally, we focus on the need to characterize AD-specific retinal Aß to differentiate Aß found in some eye diseases. Based on the current evidence, we conclude that integration of ocular biomarkers that can correctly predict brain Aß burden would have an important role as a non-invasive, yet economical surrogate marker in the diagnostic process of AD.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Fenômenos Fisiológicos Oculares/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/fisiologia , Peptídeos beta-Amiloides/fisiologia , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , Placa Amiloide/metabolismo , Proteínas tau/metabolismoRESUMO
The effects of the Alzheimer's disease (AD)-associated Amyloid-ß (Aß) peptides on platelet aggregation have been previously assessed, but most of these studies focused on Aß40 species. It also remains to be determined which distinct forms of Aß peptides exert differential effects on platelets. In AD, oligomeric Aß42 species is widely thought to be a major contributor to the disease pathogenesis. We, therefore, examine the ability of oligomeric and fibrillary Aß42 to affect platelet aggregation. We show that both forms of Aß42 induced significant platelet aggregation and that it is a novel ligand for the platelet receptor GPVI. Furthermore, a novel binding peptide that reduces the formation of soluble Aß42 oligomers was effective at preventing Aß42-dependent platelet aggregation. These results support a role for Aß42 oligomers in platelet hyperactivity.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Agregação Plaquetária/fisiologia , Testes de Função Plaquetária/métodos , HumanosRESUMO
BACKGROUND: Age-related hearing loss (ARHL) is highly prevalent in older adults, and more than two-thirds above age of 70 years suffer from ARHL. Recent studies have established a link between ARHL and cognitive impairment; however, most of the studies have used verbally loaded cognitive measures to investigate the association between ARHL and cognition. It is possible that due to hearing impairment, the elderly may experience difficulty in following verbal instructions or completing tasks that heavily rely on hearing during cognitive assessments. This may result in overestimation of cognitive impairment in such individuals. This baseline cross-sectional study investigated the associations between untreated hearing loss and a number of cognitive functions using a battery of non-verbal cognitive tests. Further, association between hearing loss and psychological status of older adults was examined. STUDY DESIGN: Prospective case-controlled study. METHODS: A total of 119 participants (54 males, M=66.33±10.50 years; 65 females M=61.51±11.46 years) were recruited. All participants completed a hearing assessment, a computerised test battery of non-verbal cognitive functions and the depression, anxiety and stress scale. RESULTS: Hierarchical multiple regression analysis results revealed that hearing thresholds significantly associated with the working memory (P<0.05), paired associative learning scores (P<0.05), depression (P<0.001), and anxiety (P<0.001) and stress (P<0.001) scores. Analysis of covariance results revealed that participants with moderately-severe hearing loss performed significantly poorer in paired associative learning and working memory tasks and psychological function tests compared to those with normal hearing. CONCLUSION: Results of the current study suggest a significant relationship between ARHL and both cognition and psychological status. Our results also have some implications for using non-verbal cognitive tests to evaluate cognitive functions in post-lingually hearing impaired ageing adults, at least for those with more than moderately-severe levels of hearing loss.
Assuntos
Envelhecimento/fisiologia , Transtornos Cognitivos/etiologia , Cognição/fisiologia , Perda Auditiva/complicações , Percepção da Fala/fisiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Estudos Transversais , Feminino , Perda Auditiva/epidemiologia , Perda Auditiva/psicologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Austrália Ocidental/epidemiologiaRESUMO
Accumulation of ß-amyloid (Aß) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (É4 carrier[É4(+)], É4 non-carrier[É4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aß-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aß neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aß positron emission tomography neuroimaging was used to classify participants as Aß(-) or Aß(+). Relative to Aß(-)É4(-), Aß(+)É4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aß(+)É4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aß(-)É4(-) and Aß(-)É4(+) groups. Among Aß(+) individuals, É4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with É4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aß-related cognitive decline. Aß(+)É4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aß(+)É4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aß(-) and Aß(+) É4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.
Assuntos
Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Compostos de Anilina/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Feminino , Seguimentos , Engenharia Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Tiazóis/metabolismoRESUMO
There is no consensus for a blood-based test for the early diagnosis of Alzheimer's disease (AD). Expression profiling of small non-coding RNA's, microRNA (miRNA), has revealed diagnostic potential in human diseases. Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum. The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients, which may aid in diagnosis. Using next-generation deep sequencing, we profiled exosomal miRNA from serum (N=49) collected from the Australian Imaging, Biomarkers and Lifestyle Flagship Study (AIBL). Sequencing results were validated using quantitative reverse transcription PCR (qRT-PCR; N=60), with predictions performed using the Random Forest method. Additional risk factors collected during the 4.5-year AIBL Study including clinical, medical and cognitive assessments, and amyloid neuroimaging with positron emission tomography were assessed. An AD-specific 16-miRNA signature was selected and adding established risk factors including age, sex and apolipoprotein É4 (APOE É4) allele status to the panel of deregulated miRNA resulted in a sensitivity and specificity of 87% and 77%, respectively, for predicting AD. Furthermore, amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD. These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , MicroRNAs/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Estudos de Casos e Controles , Exossomos/genética , Feminino , Testes Genéticos , Humanos , Masculino , Neuroimagem/métodos , Testes Neuropsicológicos , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Análise de Sequência de RNA , TranscriptomaRESUMO
The aim of this paper was to investigate the association of three well-recognised dietary patterns with cognitive change over a 3-year period. Five hundred and twenty-seven healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing completed the Cancer Council of Victoria food frequency questionnaire at baseline and underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months follow-up. Individual neuropsychological test scores were used to construct composite scores for six cognitive domains and a global cognitive score. Based on self-reported consumption, scores for three dietary patterns, (1) Australian-style Mediterranean diet (AusMeDi), (2) western diet and (3) prudent diet were generated for each individual. Linear mixed model analyses were conducted to examine the relationship between diet scores and cognitive change in each cognitive domain and for the global score. Higher baseline adherence to the AusMeDi was associated with better performance in the executive function cognitive domain after 36 months in apolipoprotein E (APOE) É4 allele carriers (P<0.01). Higher baseline western diet adherence was associated with greater cognitive decline after 36 months in the visuospatial cognitive domain in APOE É4 allele non-carriers (P<0.01). All other results were not significant. Our findings in this well-characterised Australian cohort indicate that adherence to a healthy diet is important to reduce risk for cognitive decline, with the converse being true for the western diet. Executive function and visuospatial functioning appear to be particularly susceptible to the influence of diet.
Assuntos
Transtornos Cognitivos/epidemiologia , Dieta , Idoso , Envelhecimento/genética , Envelhecimento/psicologia , Apolipoproteína E4/genética , Austrália , Transtornos Cognitivos/genética , Estudos de Coortes , Função Executiva , Feminino , Seguimentos , Humanos , Modelos Lineares , Masculino , Testes Neuropsicológicos , Análise de Componente Principal , Inquéritos e QuestionáriosRESUMO
Curcumin derived from turmeric is well documented for its anti-carcinogenic, antioxidant and anti-inflammatory properties. Recent studies show that curcumin also possesses neuroprotective and cognitive-enhancing properties that may help delay or prevent neurodegenerative diseases, including Alzheimer's disease (AD). Currently, clinical diagnosis of AD is onerous, and it is primarily based on the exclusion of other causes of dementia. In addition, phase III clinical trials of potential treatments have mostly failed, leaving disease-modifying interventions elusive. AD can be characterised neuropathologically by the deposition of extracellular ß amyloid (Aß) plaques and intracellular accumulation of tau-containing neurofibrillary tangles. Disruptions in Aß metabolism/clearance contribute to AD pathogenesis. In vitro studies have shown that Aß metabolism is altered by curcumin, and animal studies report that curcumin may influence brain function and the development of dementia, because of its antioxidant and anti-inflammatory properties, as well as its ability to influence Aß metabolism. However, clinical studies of curcumin have revealed limited effects to date, most likely because of curcumin's relatively low solubility and bioavailability, and because of selection of cohorts with diagnosed AD, in whom there is already major neuropathology. However, the fresh approach of targeting early AD pathology (by treating healthy, pre-clinical and mild cognitive impairment-stage cohorts) combined with new curcumin formulations that increase bioavailability is renewing optimism concerning curcumin-based therapy. The aim of this paper is to review the current evidence supporting an association between curcumin and modulation of AD pathology, including in vitro and in vivo studies. We also review the use of curcumin in emerging retinal imaging technology, as a fluorochrome for AD diagnostics.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/prevenção & controle , Curcumina/farmacologia , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Corantes Fluorescentes/análise , Humanos , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Ensaio Radioligante/métodos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Lower hemoglobin is associated with cognitive impairment and Alzheimer's disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-É4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Anemia/sangue , Anemia/complicações , Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Estudos Transversais , Feminino , Ácido Fólico/sangue , Hemoglobinas/metabolismo , Humanos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Transferrina/metabolismoRESUMO
Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Neocórtex/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Compostos de Anilina , Apolipoproteínas E/genética , Quimiocina CCL3/sangue , Estudos de Coortes , Proteínas Culina , Feminino , Humanos , Interleucina-17 , Masculino , Neocórtex/diagnóstico por imagem , Polipeptídeo Pancreático , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Curva ROC , TiazóisRESUMO
Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of ß amyloid (Aß) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aß levels have focused primarily on plasma Aß(1-40) and not on the more pathogenic Aß(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aß levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aß(1-40) and Aß(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aß(1-40); beta=0.208, P=0.017; Aß(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-É4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-É4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Gonadotropinas/metabolismo , Fragmentos de Peptídeos/metabolismo , Testosterona/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Apolipoproteínas E/genética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Estudos de Coortes , Humanos , Modelos Lineares , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/metabolismo , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Fatores de Risco , Estatísticas não Paramétricas , TiazóisRESUMO
Coconut, Cocos nucifera L., is a tree that is cultivated to provide a large number of products, although it is mainly grown for its nutritional and medicinal values. Coconut oil, derived from the coconut fruit, has been recognised historically as containing high levels of saturated fat; however, closer scrutiny suggests that coconut should be regarded more favourably. Unlike most other dietary fats that are high in long-chain fatty acids, coconut oil comprises medium-chain fatty acids (MCFA). MCFA are unique in that they are easily absorbed and metabolised by the liver, and can be converted to ketones. Ketone bodies are an important alternative energy source in the brain, and may be beneficial to people developing or already with memory impairment, as in Alzheimer's disease (AD). Coconut is classified as a highly nutritious 'functional food'. It is rich in dietary fibre, vitamins and minerals; however, notably, evidence is mounting to support the concept that coconut may be beneficial in the treatment of obesity, dyslipidaemia, elevated LDL, insulin resistance and hypertension - these are the risk factors for CVD and type 2 diabetes, and also for AD. In addition, phenolic compounds and hormones (cytokinins) found in coconut may assist in preventing the aggregation of amyloid-ß peptide, potentially inhibiting a key step in the pathogenesis of AD. The purpose of the present review was to explore the literature related to coconut, outlining the known mechanistic physiology, and to discuss the potential role of coconut supplementation as a therapeutic option in the prevention and management of AD.
Assuntos
Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Cocos , Dieta , Frutas/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Antioxidantes , Austrália , Encéfalo/metabolismo , Óleo de Coco , Gorduras na Dieta/administração & dosagem , Fibras na Dieta , Suplementos Nutricionais , Ácidos Graxos/análise , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Alimento Funcional , Humanos , Hiperlipidemias/terapia , Hipertensão/terapia , Resistência à Insulina , Absorção Intestinal , Corpos Cetônicos/metabolismo , Lipoproteínas LDL/sangue , Valor Nutritivo , Obesidade/terapia , Óleos de Plantas/administração & dosagem , Óleos de Plantas/química , Fatores de Risco , Relação Estrutura-AtividadeRESUMO
Western countries are experiencing aging populations and increased longevity; thus, the incidence of dementia and Alzheimer's disease (AD) in these countries is projected to soar. In the absence of a therapeutic drug, non-pharmacological preventative approaches are being investigated. One of these approaches is regular participation in physical activity or exercise. This paper reviews studies that have explored the relationship between physical activity and cognitive function, cognitive decline, AD/dementia risk and AD-associated biomarkers and processes. There is now strong evidence that links regular physical activity or exercise to higher cognitive function, decreased cognitive decline and reduced risk of AD or dementia. Nevertheless, these associations require further investigation, more specifically with interventional studies that include long follow-up periods. In particular, relatively little is known about the underlying mechanism(s) of the associations between physical activity and AD neuropathology; clearly this is an area in need of further research, particularly in human populations. Although benefits of physical activity or exercise are clearly recognised, there is a need to clarify how much physical activity provides the greatest benefit and also whether people of different genotypes require tailored exercise regimes.
Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/terapia , Cognição/fisiologia , Terapia por Exercício , Atividade Motora/fisiologia , Degeneração Neural/terapia , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Apolipoproteína E4/genética , Atrofia/patologia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Caracteres SexuaisRESUMO
Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aß42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.
Assuntos
Autofagia/efeitos dos fármacos , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , alfa-Sinucleína/antagonistas & inibidores , Peptídeos beta-Amiloides , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos , Saccharomyces cerevisiae , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidadeRESUMO
Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-ß (Aß) and Aß brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aß and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aß levels were measured in fasting blood samples. A subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aß1-42/1-40 ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aß from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ε4 carriers. Lower plasma Aß1-42/1-40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.
Assuntos
Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Atividade Motora , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Alelos , Peptídeos beta-Amiloides/sangue , Apolipoproteína E4/genética , Biomarcadores/sangue , Biomarcadores/metabolismo , Glicemia , Colesterol/sangue , Feminino , Neuroimagem Funcional , Humanos , Insulina/sangue , Estilo de Vida , Masculino , Pessoa de Meia-IdadeRESUMO
Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Autofagia/efeitos dos fármacos , Cognição/efeitos dos fármacos , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Proteína 5 Relacionada à Autofagia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Indóis/uso terapêutico , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: The prognostic value of subjective memory complaints (SMCs) in the diagnosis of dementia of the Alzheimer's type is unclear. While some studies have found an association between SMCs and cognitive decline, many have found a stronger association with depression, which raises questions about their diagnostic utility. METHODS: We examined the cross-sectional association between SMC severity (as measured using the MAC-Q, a brief SMC questionnaire) and affect, memory, and Alzheimer's disease (AD) biomarkers (ß-amyloid deposition and the apolipoprotein E ε4 (APOEε4) allele) in healthy elderly controls (HC; M = 78.74 years, SD = 6.7) and individuals with mild cognitive impairment (MCI; M = 72.74 years, SD = 8.8). We analyzed a subset of individuals drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Aging. RESULTS: SMCs were more severe in MCI patients than in HCs. SMC severity was related to affective variables and the interaction between age and group membership (HC/MCI). Within the HC group, SMC severity was related to affective variables only, while severity correlated only with age in the MCI group. SMCs were not related to cognitive variables or AD biomarkers. CONCLUSION: SMCs were related to solely by poorer mood (greater depressive and anxious symptomatology) in the cognitively healthy elderly however mean levels were subclinical. This finding argues for the assessment of affective symptomatology in conjunction with cognitive assessment in elderly memory complainers. Future AIBL research will focus on assessing other AD biomarkers, such as brain atrophy and Aß plasma markers, in relation to complaint severity. Once our 36-month follow-up data are collected, we propose to assess whether SMCs can predict future cognitive decline.
Assuntos
Envelhecimento , Doença de Alzheimer/complicações , Biomarcadores/sangue , Memória , Afeto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Austrália , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Feminino , Avaliação Geriátrica/métodos , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Prognóstico , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Pesquisa Biomédica/métodos , Ensaios Clínicos como Assunto/métodos , Genes Dominantes , Serviços de Assistência Domiciliar , Humanos , Imageamento por Ressonância Magnética , Sistemas de Medicação no Hospital , Monitorização Fisiológica/métodos , Seleção de Pacientes , Projetos de PesquisaRESUMO
OBJECTIVES: There is a growing incidence of cognitive decline and dementia associated with the ageing population. Lifestyle factors such as diet, physical activity, and cognitive activities may individually or collectively be undertaken to increase one's odds of preventing cognitive decline and future dementia. This study will examine whether clinical trials using multidomain lifestyle intervention can significantly decrease the risk of cognitive decline and therefore dementia. DESIGN, SETTING AND PARTICIPANTS: This systematic literature review of multidomain lifestyle interventions for the prevention of cognitive decline and dementia followed the PRISMA guidelines. Clinical trials involving multidomain intervention (i.e., diet and physical activity, or without cognitive training) in older adults (≥ 49 years old) at higher risk of dementia were identified through 5 electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus). A comprehensive search was performed to identify and retrieve publications until 15 November 2022. Trials were published in English. RESULTS: The included studies (n=15) assessed change in cognition in response to a multidomain lifestyle intervention. However, the cognitive outcome measures used in these studies were heterogeneous. Despite this heterogeneity, two thirds of the studies showed improvement in cognition following a multidomain intervention (n=10 with a total of 9,439 participants). However, five studies reported no improvement in cognition following the multidomain intervention. The most common form of dietary intervention included higher amount of fruit and vegetable intake; whole-grain cereal products instead of refined; low fat options in milk and meat products; and limiting sucrose intake to less than 50 g/day. Most clinical trial studies were powered to examining the effects of multidomain interventions in cognition but were not designed to test the contribution of individual domains (i.e., dietary changes, increased physical activity, or increased cognitive stimulation alone). CONCLUSION: This systematic review aimed to determine the effect of multimodal lifestyle interventions on cognitive outcomes in older adults at risk of dementia. We found that participants with conditions that may increase the risk of dementia, (e.g., hypertension, cardiovascular fragility) do benefit from multi-modal lifestyle changes including diet, physical activity, and cognitive training. Two thirds of studies using multidomain lifestyle interventions showed improvements in cognitive function. Trials with a focus on cognitive training, dietary improvement, and physical activity may prevent or delay cognitive decline in older adults including those at risk of developing dementia. Future studies should consider longer follow-up periods and adequate power to be able to examine the effects of each lifestyle component in the context of multimodal interventions.
Assuntos
Disfunção Cognitiva , Demência , Humanos , Idoso , Disfunção Cognitiva/prevenção & controle , Cognição , Dieta , Estilo de Vida , Demência/prevenção & controleRESUMO
BACKGROUND: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß and tau in predicting cognitive decline are unknown. OBJECTIVES: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aß (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). PARTICIPANTS: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. MEASUREMENTS: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aß-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. RESULTS: In CI, p217+tau was a significant predictor of change in MMSE (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU. CONCLUSIONS: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.