Plasma Proteomic Biomarkers Relating to Alzheimer's Disease: A Meta-Analysis Based on Our Own Studies.

Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer's disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers. Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals. Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc. Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation

Aquisição da coda simples e complexa com /S/ em crianças com desvio fonológico The acquisition of simple and complex coda /S/ in children with phonological disorder

OBJETIVO: descrever a produção das codas finais simples e complexa com /S/ em crianças com desvio fonológico e verificar a influência de variáveis linguísticas e extralinguísticas na aquisição das mesmas. MÉTODO: foram utilizados dados de fala de 66 crianças com desvio fonológico, 33 meninos e 33 meninas, entre 3:0 e 9:0. As amostras de fala foram coletadas transversalmente, com base no instrumento Avaliação Fonológica da Criança. Foram analisadas apenas as palavras alvo contendo coda simples lexical (ex.: talvez), coda simples morfológica (ex.: casas), coda complexa composta por nasal e fricativa (ex.: parabéns) e coda complexa com glide e fricativa (ex.: dois), totalizando um corpus de 481 palavras. Para ambos os tipos de coda foram consideradas como variáveis dependentes a produção correta do /S/, a omissão da coda ou sua substituição. Como variáveis intervenientes consideraram-se os fatores extralinguísticos idade, sexo e grau do desvio e as variáveis linguísticas classe gramatical, tonicidade, número de sílabas, contexto precedente e tipo de coda. Os dados de fala foram analisados estatisticamente através do VARBRUL, com grau de significância de 5%. RESULTADO: o programa estatístico selecionou como significante para a produção correta das codas simples e complexas as variáveis classe gramatical, tipo de coda e a gravidade do desvio em ordem decrescente de relevância estatística, com valor de p < 0,001. CONCLUSÃO: verificou-se que as variáveis gravidade do desvio, tipo de coda e classe gramatical influenciam de forma significante a produção das codas finais simples e complexas com o arquifonema /S/, em crianças com desvio fonológico.<br>PURPOSE: to describe the production of final simple and complex coda with /S/ in children with phonological disorder, verifying the influence of linguistic and extra-linguistic variables in codas acquisition. METHOD: we utilized speech data from 66 children with phonological disorder, 33 boys and 33 girls, aged between 3:0 and 9:0. Speech samples were collected through a crossed-nature study, using the instrument referred to as Child Phonological Evaluation¹, with 481 words being part of the database from a project which was approved by the Ethics Research Committee (CEP) of the institution. Next, the words were statistically analyzed through the statistical program VARBRUL, considering a significance level of 5%. We took into account as dependent variables the correct production of /S/, the omission of the coda or its substitution. As intervening variable, we considered the extra-linguistic factors age, sex, degree of the phonological disorder; and the linguistic variables grammatical class, tonicity, precedent context, and type of coda. RESULTS: the statistical program selected as statistically significant for the correct production of simple and complex coda, the degree of the phonological disorder, the type of coda, and the grammatical class, with the value of p < 0.01. CONCLUSION: we verified, through this study, that the degree of phonological disorder, type of coda, and grammatical class influenced in a significant way on the production of final simple and complex coda with the archiphoneme /S/, in children with phonological disorder

Replication study of plasma proteins relating to Alzheimer's pathology.

This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis

Validation of plasma proteomic biomarkers relating to brain amyloid burden in the EMIF-Alzheimer's disease multimodal biomarker discovery cohort

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure

Validation of plasma proteomic biomarkers relating to brain amyloid burden in the EMIF-Alzheimer's disease multimodal biomarker discovery cohort

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer’s disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure