RESUMO
Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-ß and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.
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Doença de Alzheimer , Disfunção Cognitiva , Doenças Neurodegenerativas , Ácido 3-Hidroxiantranílico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Austrália , Biomarcadores , Disfunção Cognitiva/líquido cefalorraquidiano , Estudos Transversais , Progressão da Doença , Humanos , Cinurenina , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
We fractionated frontal cortical grey matter from human Alzheimer's disease and control subjects into four biochemically defined pools that represent four distinct compartments: soluble/cytosolic, peripheral membrane/vesicular cargo, integral lipid/membranous pools and aggregated/insoluble debris. Most of the readily extractable amyloid-ß remains associated with a lipid/membranous compartment. There is an exchange of amyloid-ß between the biochemical pools that was lost for the amyloid-ß42 species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-ß data, combined with magnetic resonance imaging volumetric analysis of the amount of cortical grey matter in brain, allowed us to estimate the total mass of amyloid-ß in Alzheimer's disease (6.5 mg) and control (1.7 mg) brains. The threshold positron emission tomography standard uptake value ratio of 1.4 equates to 5.0 µg amyloid-ß/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 µg amyloid-ß/g of grey matter. It takes 19 years to accumulate amyloid from the threshold positron emission tomography standard uptake value ratio to the mean value observed for Alzheimer's disease dementia. This accumulation time window combined with the difference of 4.8 mg of amyloid-ß between Alzheimer's disease and control brain allows for a first approximation of amyloid-ß accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-ß production being deposited as insoluble plaques. Understanding these rates of amyloid-ß accumulation allows for a more quantitative approach in targeting the failure of amyloid-ß clearance in sporadic Alzheimer's disease.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Lobo Frontal/metabolismo , Substância Cinzenta/metabolismo , Placa Amiloide/metabolismo , Doença de Alzheimer/patologia , Estudos de Casos e Controles , Lobo Frontal/patologia , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética , Neuroimagem , Tomografia por Emissão de Pósitrons , Fatores de TempoRESUMO
OBJECTIVE: Several studies have reported that non-demented older adults with clinical depression show changes in amyloid-ß (Aß) levels in blood, cerebrospinal fluid and on neuroimaging that are consistent with those observed in patients with Alzheimer's disease. These findings suggest that Aß may be one of the mechanisms underlying the relation between the two conditions. We sought to determine the relation between elevated cerebral Aß and the presence of depression across a 54-month prospective observation period. METHODS: Cognitively normal older adults from the Australian Imaging Biomarkers and Lifestyle study who were not depressed and had undergone a positron emission tomography scan to classify them as either high Aß (n = 81) or low Aß (n = 278) participated. Depressive symptoms were assessed using the Geriatric Depression Scale - Short Form at 18-month intervals over 54 months. RESULTS: Whilst there was no difference in probable depression between groups at baseline, incidence was 4.5 (95% confidence interval [CI] 1.3-16.4) times greater within the high Aß group (9%) than the low Aß group (2%) by the 54-month assessment. CONCLUSIONS: Results of this study suggest that elevated Aß levels are associated with a 4.5-fold increased likelihood of developing clinically significant depressive symptoms on follow-up in preclinical Alzheimer's disease. This underscores the importance of assessing, monitoring and treating depressive symptoms in older adults with elevated Aß. Copyright © 2016 John Wiley & Sons, Ltd.
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Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Biomarcadores/análise , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neuroimagem , Tomografia por Emissão de Pósitrons , Estudos ProspectivosRESUMO
Sporadic Alzheimer's disease (AD) is characterised by the deposition and accumulation of specific protein aggregates. Failure of clearance could underlie this process, and recent genetic association studies point towards involvement of the phagocytosis and autophagy pathways. We developed a real-time tri-color flow cytometry method to quantitate the phagocytic function of human peripheral blood monocyte subsets including non-classic CD14(dim)CD16(+), intermediate CD14(+)CD16(+) and classic CD14(+)CD16(-) monocytes. Using this method, we have measured the phagocytic ability of fresh monocytes in a study of preclinical, prodromal and clinical AD, matched with cognitively normal healthy control subjects. Basal levels of phagocytosis in all three subsets of monocytes were similar between healthy controls and AD patients, while a significant increase of basal phagocytosis was found in subjects with high Aß-amyloid burden as assessed by PET scans. Pre-treating cells with Copaxone (CPX, to stimulate phagocytosis) or ATP (an inhibitor of P2X7-mediated phagocytosis) showed a differential response depending on clinical or Aß-burden status, indicating a relative functional deficit. Overall the results are consistent with a perturbation of basal and stimulated innate phagocytosis in sporadic AD.
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Doença de Alzheimer/metabolismo , Monócitos/metabolismo , Fagocitose/imunologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/imunologia , Proteínas Amiloidogênicas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Receptores de IgG/imunologia , Receptores de IgG/metabolismoRESUMO
FFQ are commonly used to examine the association between diet and disease. They are the most practical method for usual dietary data collection as they are relatively inexpensive and easy to administer. In Australia, the Cancer Council of Victoria FFQ (CCVFFQ) version 2 and the online Commonwealth Scientific and Industrial Research Organisation FFQ (CSIROFFQ) are used. The aim of our study was to establish the level of agreement between nutrient intakes captured using the online CSIROFFQ and the paper-based CCVFFQ. The CCVFFQ and the online CSIROFFQ were completed by 136 healthy participants. FFQ responses were analysed to give g per d intake of a range of nutrients. Agreement between twenty-six nutrient intakes common to both FFQ was measured by a variety of methods. Nutrient intake levels that were significantly correlated between the two FFQ were carbohydrates, total fat, Na and MUFA. When assessing ranking of nutrients into quintiles, on average, 56 % of the participants (for all nutrients) were classified into the same or adjacent quintiles in both FFQ, with the highest percentage agreement for sugar. On average, 21 % of participants were grossly misclassified by three or four quintiles, with the highest percentage misclassification for fibre and Fe. Quintile agreement was similar to that reported by other studies, and we concluded that both FFQ are suitable tools for dividing participants' nutrient intake levels into high- and low-consumption groups. Use of either FFQ was not appropriate for obtaining accurate estimates of absolute nutrient intakes.
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Dieta , Neoplasias , Inquéritos e Questionários , Idoso , Idoso de 80 Anos ou mais , Austrália , Registros de Dieta , Inquéritos sobre Dietas , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Fibras na Dieta/administração & dosagem , Ingestão de Energia , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Alimentos , Humanos , Ferro da Dieta/administração & dosagem , Masculino , Pessoa de Meia-Idade , Avaliação Nutricional , Pesquisa , Ciência , Sódio na Dieta/administração & dosagem , VitóriaRESUMO
BACKGROUND: Information provided by an informant about a patient with cognitive change is an essential component of clinical history taking. How an informant's report relates to the patient's phenomenological experience of memory loss is yet to be understood. The aim was to examine patterns of relationships between self and informant reports from a phenomenological perspective. METHODS: Forty-three healthy non-memory complainers (HC-NMC), 37 healthy subjective memory complainers (HC-SMC) and 43 individuals with mild cognitive impairment (MCI) were administered a semi-structured interview, which measured their concerns of frequency of memory lapses and impact on mood. Informants responded to questionnaires. RESULTS: Self-reported concerns of increasing frequency and impacted mood related to informant concerns in HC-SMCs. MCI with lower informant concern showed a similar pattern to HC-SMCs on complaints of increasing frequency. In those with higher informant concern, self-reports markedly separated from informant concern. The MCI group with greater informant concern performed comparatively poor on verbal and non-verbal memory measures. CONCLUSIONS: Our results suggest that the association between self-reported and informant memory concerns is moderated by MCI severity. Self and informant reports of increasing memory lapse frequency aligned in HC-SMC and MCIs with low informant concern, suggesting a similar dyadic experience of memory change. In MCIs with greater informant concern, the pattern changed exposing a changing insight with advancing memory impairment. These individuals are potentially reflecting a 'forgetting that they forget' phenomenon in elements of their concern.
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Transtornos Cognitivos/psicologia , Disfunção Cognitiva/psicologia , Transtornos da Memória/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Transtornos Cognitivos/diagnóstico , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Entrevistas como Assunto , Masculino , Transtornos da Memória/diagnóstico , Pessoa de Meia-Idade , Autorrelato , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Autobiographical memory (ABM), personal semantic memory (PSM), and autonoetic consciousness are affected in individuals with mild cognitive impairment (MCI) but their relationship with Alzheimer's disease (AD) biomarkers are unclear. METHODS: Forty-five participants (healthy controls (HC) = 31, MCI = 14) completed the Episodic ABM Interview and a battery of memory tests. Thirty-one (HC = 22, MCI = 9) underwent ß-amyloid positron emission tomography (PET) and magnetic resonance (MR) imaging. Fourteen participants (HC = 9, MCI = 5) underwent one imaging modality. RESULTS: Unlike PSM, ABM differentiated between diagnostic categories but did not relate to AD biomarkers. Personal semantic memory was related to neocortical ß-amyloid burden after adjusting for age and apolipoprotein E (APOE) É4. Autonoetic consciousness was not associated with AD biomarkers, and was not impaired in MCI. CONCLUSIONS: Autobiographical memory was impaired in MCI participants but was not related to neocortical amyloid burden, suggesting that personal memory systems are impacted by differing disease mechanisms, rather than being uniformly underpinned by ß-amyloid. Episodic and semantic ABM impairment represent an important AD prodrome.
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Doença de Alzheimer/diagnóstico , Memória Episódica , Idoso , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/análise , Biomarcadores/análise , Química Encefálica , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória , Transtornos da Memória/diagnóstico , Transtornos da Memória/psicologia , Neuroimagem , Testes Neuropsicológicos , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 individuals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of individuals who transitioned to a more severe disease stage compared with those who did not. METHODS: Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood sample, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging. RESULTS: The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%. CONCLUSION: There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.
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Envelhecimento/patologia , Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/psicologia , Doença de Alzheimer/sangue , Austrália , Biomarcadores/sangue , Estudos de Casos e Controles , Cognição , Disfunção Cognitiva/sangue , Feminino , Seguimentos , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos/estatística & dados numéricos , Estudos Prospectivos , Fatores SocioeconômicosRESUMO
BACKGROUND: A practical biomarker is required to facilitate the preclinical diagnosis of Alzheimer's disease (AD). METHODS: Plasma amyloid beta (Aß)1-40, Aß1-42, Aßn-40, and Aßn-42 peptides were measured at baseline and after 18 months in 771 participants from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging. Aß peptide levels were compared with clinical pathology, neuroimaging and neuropsychological measurements. RESULTS: Although inflammatory and renal function covariates influenced plasma Aß levels significantly, a decrease in Aß1-42/Aß1-40 was observed in patients with AD, and was also inversely correlated with neocortical amyloid burden. During the 18 months, plasma Aß1-42 decreased in subjects with mild cognitive impairment (MCI) and in those transitioning from healthy to MCI. CONCLUSION: Our findings are consistent with a number of published plasma Aß studies and, although the prognostic value of individual measures in any given subject is limited, the diagnostic contribution of plasma Aß may demonstrate utility when combined with a panel of peripheral biomarkers.
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Envelhecimento/sangue , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Fragmentos de Peptídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Distribuição de Qui-Quadrado , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico por imagem , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de PósitronsRESUMO
The formation of low-order oligomers of ß-amyloid (Aß) within the brain is widely believed to be a central component of Alzheimer's disease (AD) pathogenesis. However, despite advances in high-throughput and high-resolution techniques such as xMAP and mass spectrometry (MS), investigations into these oligomeric species have remained reliant on low-resolution Western blots and enzyme-linked immunosorbent assays. The current investigation compared Aß profiles within human cortical tissue using sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis (PAGE), xMAP and surface enhanced laser desorption/ionization time-of-flight MS and found that whilst there was significant correlation across the techniques regarding levels of monomeric Aß, only SDS-PAGE was capable of detecting dimeric isoforms of Aß. The addition of synthetic di-tyrosine cross-linked Aß(1-40)Met(35)(O) to the AD tissue demonstrated that the MS methodology was capable of observing dimeric Aß at femto-molar concentrations, with no noticeable effect on monomeric Aß levels. Focus turned to the association between SDS-PAGE and levels of observable dimeric Aß within the AD brain tissue. These investigations revealed that increased levels of dimeric Aß were observed with increasing concentrations of SDS in the sample buffer. This finding was subsequently confirmed using synthetic Aß(1-42) and suggests that SDS was inducing the formation of dimeric Aß. The findings that SDS promotes Aß dimerization have significant implications for the putative role of low-order oligomers in AD pathogenesis and draw into question the utility of oligomeric Aß as a therapeutic target.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Artefatos , Encéfalo/metabolismo , Eletroforese em Gel de Poliacrilamida , Doença de Alzheimer/patologia , Encéfalo/patologia , Dimerização , HumanosRESUMO
The Australian Imaging Biomarkers and Lifestyle (AIBL) study is a longitudinal study of 1,112 volunteers from healthy, mild cognitive impairment (MCI) and Alzheimer's disease (AD) populations who are assessed at 18-month intervals in order to enable prospective research into ageing and AD. Using a multidisciplinary battery, AIBL assessments comprise the extensive study of clinical factors and cognitive function, collection of blood and cerebrospinal fluid (CSF) samples for biomarker discovery, structural and ß-amyloid (Aß) neuroimaging, and obtaining information on diet and physical activity patterns of the cohort. Now in its seventh year, AIBL is part of a substantial international effort to prospectively study the relationships between clinical characteristics and putative AD biomarkers in groups who carry different risk factors for AD. The identification of biomarkers would provide a window of opportunity to assess AD risk in individuals prior to the onset of advanced clinical symptoms, in addition to facilitating testing of therapeutic and lifestyle interventions likely to emerge within the next decade that prevent or delay symptom emergence in those at high risk for developing AD. In this paper, we present key findings from the AIBL study and discuss how they contribute to our understanding of AD pathogenesis and diagnosis.
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Envelhecimento/patologia , Doença de Alzheimer/diagnóstico , Neuroimagem , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/efeitos adversos , Apolipoproteína E4/efeitos adversos , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Humanos , Estudos Longitudinais , Neuroimagem/métodosRESUMO
Accumulation of the amyloid ß peptide in the cortical and hippocampal regions of the brain is a major pathological feature of Alzheimer disease. Amyloid ß peptide is generated from the sequential protease cleavage of the amyloid precursor protein (APP). We reported previously that copper increases the level of APP at the cell surface. Here we report that copper, but not iron or zinc, promotes APP trafficking in cultured polarized epithelial cells and neuronal cells. In SH-SY5Y neuronal cells and primary cortical neurons, copper promoted a redistribution of APP from a perinuclear localization to a wider distribution, including neurites. Importantly, a change in APP localization was not attributed to an up-regulation of APP protein synthesis. Using live cell imaging and endocytosis assays, we found that copper promotes an increase in cell surface APP by increasing its exocytosis and reducing its endocytosis, respectively. This study identifies a novel mechanism by which copper regulates the localization and presumably the function of APP, which is of major significance for understanding the role of APP in copper homeostasis and the role of copper in Alzheimer disease.
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Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/biossíntese , Cobre/metabolismo , Neuritos/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular , Cobre/farmacologia , Cães , Endocitose/efeitos dos fármacos , Endocitose/genética , Humanos , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer's disease dementia (AD)) as an 'Inception cohort' who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an 'Enrichment cohort' (as of 10 April 2019). OBJECTIVE: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. METHODS: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. RESULTS: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aß-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. CONCLUSION: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.
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BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial. OBJECTIVE: Assessing levels of Aß-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aß-amyloid (32 Aß-amyloid-and 45 Aß-amyloid+), as well as concordance between CSF biomarker levels and PET Aß-amyloid imaging. METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging. RESULTS: Across all three platforms, the T-tau/Aß42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ=â0.69-0.8) as compared with Aß42 alone (ρ=â0.66-0.75). Differences in CSF biomarker levels between the PET Aß-amyloid-and Aß-amyloid+ groups were strongest for the Aß42/Aß40 and T-tau/Aß42 ratios (pâ<â0.0001); however, comparison of predictive models for PET Aß-amyloid showed no difference between Aß42 alone and the T-tau/Aß42 ratio. CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aß-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/patologia , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Curva ROC , Proteínas tau/líquido cefalorraquidianoRESUMO
Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-ß peptide (also known as Aß or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aß peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E É4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aß.
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Doença de Alzheimer/diagnóstico , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Austrália/epidemiologia , Biomarcadores/metabolismo , Humanos , Estresse Oxidativo/fisiologiaRESUMO
INTRODUCTION: We are developing a second generation 8-OH quinoline (2-(dimethylamino) methyl-5, 7-dichloro-8-hydroxyquinoline [PBT2, Prana Biotechnology]) for targeting amyloid ß (Aß) in Alzheimer's disease (AD). In an earlier phase IIa, 3 month trial, PBT2 lowered cerebrospinal fluid Aß by 13% and improved cognition (executive function) in a dose-related fashion in early AD. We, therefore, sought to learn whether PBT2 could alter the Aß-PET signal in subjects with prodromal or mild AD, in an exploratory randomized study over a 12-month phase in a double-blind and a 12-month open label extension phase trial design. METHODS: For inclusion, the usual clinical criteria for prodromal or probable AD, Mini-Mental State Examination ≥20, and global Pittsburgh compound B (PiB)-PET standardized uptake volume ratio (SUVR) >1.7 were used. As this was an exploratory study, we included contemporaneous matched control data from the Australian Imaging Biomarker and Lifestyle Study (AIBL). Other measures included fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging volumetrics, blood Aß biomarkers, and cognition and function. RESULTS: Forty subjects completed the first 12-month double-blind phase (placebo = 15, PBT2 = 25), and 27 subjects completed the 12-month open label extension phase (placebo = 11, PBT2 = 16). Overall, PTB2 250 mg/day was safe and well tolerated. The mean PiB-PET SUVR at baseline was 2.51 ± 0.59. After adjusting for baseline SUVR, in the double-blind phase, the placebo group showed a nonsignificant decline in PiB-PET SUVR, whereas the PBT2 group declined significantly (P = .048). Subjects who did not enter or complete the extension study had a significantly higher 12-month Aß-PET SUVR (2.68 ± 0.55) compared with those who completed (2.29 ± 0.48). Both groups differed significantly from the rate of change over 12 months in the AIBL control group. In the open label 12-month extension study, the PiB-SUVR stabilized. There were no significant differences between PBT2 and controls in fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging volumetrics, blood Aß biomarkers, or cognition/function over the course of the double-blind phase. DISCUSSION: There was no significant difference between PBT2 and controls at 12 months, likely due to the large individual variances over a relatively small number of subjects. PBT2 was associated with a significant 3% PiB-PET SUVR decline in the double-blind phase and a stabilization of SUVR in the open-label phase. From this exploratory study, we have learned that the entry criterion of SUVR should have been set at ≥ 1.5 and <2.0, where we know from the AIBL study that subjects in this band are accumulating Aß in a linear fashion and that subjects who withdrew from this type of study have much higher SUVRs, which if not taken into account, could distort the final results. Because of large individual variations in SUVR, future studies of PBT2 will require larger numbers of subjects (n > 90 per arm) over a longer period (18 months or more). Further evaluation of higher doses of PBT2 in earlier stages of AD is warranted. TRIAL REGISTRATION: ACTRN 12611001008910 and ACTRN 12613000777796.
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Mutations in the intracellular metalloenzyme superoxide dismutase 1 (SOD1) are linked to neurotoxicity in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism. Golgi fragmentation and endoplasmic reticulum stress are early hallmarks of spinal motor neuron pathology in transgenic mice overexpressing mutant SOD1, suggesting that dysfunction of the neuronal secretory pathway may contribute to ALS pathogenesis. We therefore proposed that mutant SOD1 directly engages and modulates the secretory pathway based on recent evidence of SOD1 secretion in diverse human cell lines. Here, we demonstrate that a fraction of active endogenous SOD1 is secreted by NSC-34 motor neuron-like cells via a brefeldin-A (BFA)-sensitive pathway. Expression of enhanced green fluorescent protein-tagged mutant human SOD1 (hSOD1-EGFP) in NSC-34 cells induced frequent cytoplasmic inclusions and protein insolubility that correlated with toxicity. In contrast, transfection of non-neuronal COS-7 cells resulted in mutant hSOD1-EGFP cytoplasmic inclusions, oligomerization, and fragmentation without detectable toxicity. Importantly, impaired secretion of hSOD1-EGFP was common to all 10 SOD1 mutants tested relative to wild-type protein in NSC-34 cells. Treatment with BFA inhibited hSOD1-EGFP secretion with pronounced BFA-induced toxicity in mutant cells. Extracellular targeting of mutant hSOD1-EGFP via SOD3 signal peptide fusion attenuated cytoplasmic inclusion formation and toxicity. The effect of elevated extracellular SOD1 was then evaluated in a transgenic rat model of ALS. Chronic intraspinal infusion of exogenous wild-type hSOD1 significantly delayed disease progression and endpoint in transgenic SOD1(G93A) rats. Collectively, these results suggest novel extracellular roles for SOD1 in ALS and support a causal relationship between mutant SOD1 secretion and intraneuronal toxicity.
Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/patologia , Neurônios Motores/enzimologia , Neurônios Motores/patologia , Superóxido Dismutase/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Animais Geneticamente Modificados , Células COS , Células Cultivadas , Chlorocebus aethiops , Modelos Animais de Doenças , Humanos , Corpos de Inclusão/patologia , Camundongos , Movimento/fisiologia , Mutação , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão , Superóxido Dismutase/genética , Superóxido Dismutase-1RESUMO
Metals are increasingly recognized to have an important role in molecular processes underlying Alzheimer's disease (AD). This chapter discusses the current role of metals in AD and expands on the development of metalloproteomics and how the recent advances in analytical technology will allow detailed investigation of metalloproteins. Investigation of individual metalloproteins will yield new mechanistic details about the role of metals in AD.