Parkinson's and Lewy body dementia CSF biomarkers

Parnetti, Lucilla; Paciotti, Silvia; Farotti, Lucia; Bellomo, G.; Sepe, Federica Nicoletta

doi:10.1016/j.cca.2019.04.078

Cited by 42 publications

(29 citation statements)

References 113 publications

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“…Reduced Aβ42 levels have been found in AD-CSF (Ahmed et al, 2014) and tau and neurofilament are elevated in AD-plasma and CSF compared with controls (Zetterberg et al, 2013). Although classical AD CSF biomarkers have been explored as potential differential diagnosis tools in DLB patients, results from studies are controversial (Parnetti et al, 2019), and no peripheral biomarkers that differentiate between DLB and AD have been identified so far.…”

Section: Introductionmentioning

confidence: 99%

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Gámez-Valero

Campdelacreu

Vilas

et al. 2020

Preprint

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_ 3 The paper explained Problem: Dementia with Lewy bodies (DLB) presents pathological and clinical overlap with both Alzheimer's (AD) and Parkinson's disease (PD), which impairs its correct diagnosis. Although numerous papers report peripheral biomarkers for AD, wellestablished biomarkers for DLB distinguishing it from AD are still missing. Platelet miRNA transcriptome was analyzed in several works, but their putative role as disease biomarkers for neurological disorders has not been assessed. It would be of paramount importance to establish a blood-based bio-signature as a minimally invasive mean for DLB diagnosis, improving differentiation of DLB patients from controls and AD. Results:Our study revealed that platelet miRNAs might be promising biomarkers for the correct diagnosis of DLB stratifying patients in comparison with overlapping disorders, especially AD, and may help to highlight possible disease-related processes.In this cross-sectional study, which includes 162 individuals (DLB, AD, PD and healthy controls), platelet-associated miRNA content was disease group-specific. Three different miRNA sets together with their predicted targeted pathways were defined. Impact:This study suggests that platelet miRNA may serve as DLB biomarker allowing the correct diagnosis and stratification in an easily-applied manner in clinical settings, and may help to highlight possible disease-related processes. 4 ABSTRACT Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia after Alzheimer's disease (AD) and presents pathological and clinical overlap with both AD and Parkinson's disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets, previously related to neurodegeneration, contain microRNAs (miRNAs) whose analysis may provide disease biomarkers. Here, we profiled the whole platelet miRNA transcriptome from DLB patients and healthy controls. Differentially expressed miRNAs were further validated in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Results comprised a 7-miRNA biosignature, showing the highest diagnostic potential for the differentiation between DLB and AD. Additionally, compared to controls, two miRNAs were down-regulated in DLB, four miRNAs were up-regulated in AD, and two miRNAs were down-regulated in PD. Predictive target analysis identified three disease-specific clusters of pathways as a result of platelet-miRNA deregulation. Our cross-sectional study assesses the identification of a novel, highly specific and sensitive platelet-associated miRNA-based bio-signature, which distinguishes DLB from AD.

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Section: Introductionmentioning

confidence: 99%

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Gámez-Valero

Campdelacreu

Vilas

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Moreover, in many amyloidopathies, the CSF levels of the soluble peptides/proteins that eventually form amyloid aggregates decrease rather than increase (Kang, 2016;Hu et al, 2017). In AD and PD, the decrease in CSF levels of soluble Aβ (Fagan et al, 2009;Bateman et al, 2012;Buchhave et al, 2012) and α-syn (Tokuda et al, 2006;Wang et al, 2015;Mollenhauer et al, 2019;Parnetti et al, 2019) is among the early biochemical markers of the disease. A similar downward trend is observed for the CSF levels of soluble PrP in CJD (Meyne et al, 2009;Dorey et al, 2015).…”

Section: Gain or Loss Of Function?mentioning

confidence: 99%

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

et al. 2020

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Amyloids are fibrillar protein aggregates associated with diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes and Creutzfeldt-Jakob disease. The process of amyloid polymerization involves three pathological protein transformations; from natively folded conformation to the cross-β conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-β conformation, the biophysical transformation can either take place spontaneously via a homogeneous nucleation mechanism (HON) or catalytically on an exogenous surface via a heterogeneous nucleation mechanism (HEN). Here, we postulate that the different nucleation pathways can serve as a mechanistic basis for an etiological classification of amyloidopathies, where hereditary forms generally follow the HON pathway, while sporadic forms follow seed-induced (prions) or surface-induced (including microbially induced) HEN pathways. Critically, the conformational and biophysical amyloid transformation results in loss-of-function (LOF) of the original natively folded and soluble protein. This LOF can, at least initially, be the mechanism of amyloid toxicity even before amyloid accumulation reaches toxic levels. By highlighting the important role of non-protein species in amyloid formation and LOF mechanisms of toxicity, we propose a generalized mechanistic framework that could help better understand the diverse etiology of amyloid diseases and offer new opportunities for therapeutic interventions, including replacement therapies.

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“…Reduced Aβ42 levels have been found in AD-CSF [5] and tau and neuro lament are elevated in AD-plasma and CSF compared with controls [6]. Although classical AD CSF biomarkers have been explored as potential differential diagnosis tools in DLB patients, results from studies are controversial [7], and no peripheral biomarkers that differentiate between DLB and AD have been identi ed so far.…”

Section: Page 3/25mentioning

confidence: 99%

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease: A cross-sectional study.

Gámez-Valero

Campdelacreu

Vilas

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia after Alzheimer’s disease (AD) and presents pathological and clinical overlap with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets have been previously related to neurodegeneration. They contain microRNAs (miRNAs), and their analysis may provide disease biomarkers. Methods Small RNAs from platelets of DLB patients and controls were analyzed by Next Generation Sequencing (NGS), and miRNAs deregulated in DLB were selected. Expression of these miRNAs was then determined and validated by LNA-based qRT-PCR in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Their predictive diagnostic potential was calculated by ROC curve analysis. miRTarbase and miRGate were used for target prediction. Results We profiled the whole platelet miRNA transcriptome from 7 DLB patients and 7 controls using NGS. Twenty-two selected miRNAs were further validated in independent studies (2017–2019) including DLB (n = 59), AD (n = 28), and PD (n = 24) patients, and control individuals (n = 51). Our results demonstrated downregulated expression levels for hsa-let-7d-5p (fold change 0.14; p = 0.006), hsa-miR-132-5p (0.12; p = 0.0015), hsa-miR-142-3p (0.07; p = 0.00047), hsa-miR-146a-5p (0.07; p = 0.00035), hsa-miR-150-5p (0.10; p = 0.0098), hsa-miR-25-3p (0.13; p = 0.0019) and hsa-miR-26b-5p (0.09; p = 0.0014) in DLB compared to AD. ROC curve for this seven-miRNA biosignature yielded an area under the curve (AUC) of 1. Both hsa-miR-142-3p and hsa-miR-150-5p, were down-regulated in DLB compared to controls (AUC = 0.85). Comparing AD and controls, miRNAs hsa-miR-132-5p, hsa-miR-146a-5p, hsa-miR-25-3p, and hsa-miR-6747-3p were up-regulated in AD (AUC = 0.94); and hsa-miR-128-3p and hsa-miR-139-5p were down-regulated in PD compared to controls (AUC = 0.81). Predictive target analysis identified three disease-specific pathway clusters as a result of platelet-miRNA deregulation. In DLB, pathways related to gene expression and small RNA metabolism; in AD, pathways related to stress response and RNA stress granules; and in PD pathways related to protein phosphorylation, metabolism and degradation were identified. Conclusion A platelet-associated bio-signature composed of 7 miRNAs is highly specific and sensitive for distinguishing DLB from AD.

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Parkinson's and Lewy body dementia CSF biomarkers

Cited by 42 publications

References 113 publications

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease: A cross-sectional study.

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