Plasma proteome profiling identifies changes associated to AD but not to FTD

Abstract

Background Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. Methods Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. Results Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. Conclusions We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.

Glycoprotein 1b (GP1b) protein, miR-26a-5p levels and platelet function in Alzheimer’s Disease

“…The differential expressions of miRNAs have been extensively studied in a variety of disorders including AD indicating the promising roles of miRNAs as therapeutic targets and biomarkers [14]. Previous studies already reported the comparison of levels of GP1b and vWF in AD [33], [34], [35], [36], [37], [38], [39], however, the relationship between platelet function of the regulatory mechanism of these two proteins in AD pathogenesis has not been elucidated yet. Therefore, in this study, we not only compared the levels of GP1b and vWF proteins in AD patients but also to clarify the molecular regulation mechanism of these two proteins, we compared the expression levels of hsa-miR-24-3p and hsa-miR-26a-5p to investigate the association with platelet function and AD.…”

“…Also Yavuz B.B et al compared the vWF antigen levels in healthy subjects and AD and they did not nd signi cant differences in the vWF antigen levels in controls compared to AD [8]. Since vWF is a biomarker of vascular damage, the role of vWF is the focus of research studies in the pathogenesis of AD [35]. However, results of vWF levels in AD patients have been con icting.…”

CSF Proteomics in Patients With Progressive Supranuclear Palsy

“…9,10 SOMAmer proteomics has been successfully used in biomarker discovery in plasma or CSF in cancer, 11 aging, 12 and Alzheimer disease (AD). [13][14][15] In this study, we used SOMAmer proteomics for multiplexed analysis of the CSF proteome in 2 independent PSP-RS clinical cohorts, PSP neuropathology-confirmed and non-PSP FTLD neuropathology-confirmed disease cases, and cognitively healthy controls. We hypothesized that SOMAmer CSF proteomics would identify distinctive signatures in PSP, potentially providing insight into disease pathobiology and new candidate biomarkers and therapeutic targets.…”

“…9,10 SOMAmer proteomics has been successfully used in biomarker discovery in plasma or CSF in cancer, 11 aging, 12 and Alzheimer disease (AD). 13-15…”

Multiomic approach and Mendelian randomization analysis identify causal associations between blood biomarkers and subcortical brain structure volumes

“…Finally, the human microbiota play an important role in the fermentation of nondigestible substrates as well as providing protection against foreign pathogens [17,18]. A number of studies have found that changes in the level of different proteins, metabolites and the composition of the gut microbiome are associated with different metabolic, immunological as well as neurological disorders [19][20][21][22]. The importance of the level of different metabolites such as glucose, lactate and pyruvate in the cerebrospinal fluid (CSF) is well known and they are established biomarkers to study inflammation and malignancies in the brain [23].…”