Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases

Seino, Yusuke; Nakamura, Takumi; Kawarabayashi, Tatsuhiko; Hirohata, Mie; Narita, Sakiko; Wakasaya, Yasuhito; Kaito, Kozue; Ueda, Tetsuya; Harigaya, Yasuo; Shoji, Mikio

doi:10.3233/jad-181152

Cited by 29 publications

(21 citation statements)

References 38 publications

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“…That, combined with recent reports of acceptable diagnostic performance of plasma A␤ when measured using different high-throughput tech-niques [8,30], leads us to suggest that the assay may have failed to produce accurate plasma A␤ data. Technical issues in our study were also indicated by the fact that plasma A␤ relative to CSF A␤ was far lower than the expected 10-fold difference [22] our >20-fold difference mirrored that of another investigation which also found no association of plasma A␤ with cognitive status [36].…”

Section: Discussionsupporting

confidence: 65%

“…The goal should be to standardize analysis methods across labs. Here, we did not create CSF/plasma A␤ ratios, because AD diagnosis was based in part on CSF A␤ so that such ratios would have led to circular arguments, but future studies could explore their usefulness (e.g., [36]) as well as ratios combining several plasma biomarkers (e.g., [62]).…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have found an association of lower plasma A␤ concentrations (thought to reflect a greater brain A␤ burden) with more severe neuropsychological deficits [23,24], with an increased risk of developing AD [25,26], and with amyloidpositive PET [8,27,28] or amyloid-abnormal CSF [29,30] as current gold standards for AD diagnosis. Others report results in the opposite direction [31][32][33][34] and null findings, too, are frequent [35][36][37]. It has been suggested that one reason for this inconsistency may lie in between-study differences in the cognitive profiles of study samples given that plasma A␤ levels follow a complex temporal trajectory: concentrations increase with age but, potentially due to brain A␤ aggregation, reduce in symptomatic stages of AD [22,32,38].…”

Section: Introductionmentioning

confidence: 99%

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Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls

Feinkohl

Schipke

Kruppa

et al. 2020

JAD

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Background: Collection of cerebrospinal fluid (CSF) for measurement of amyloid-␤ (A␤) species is a gold standard in Alzheimer's disease (AD) diagnosis, but has risks. Thus, establishing a low-risk blood A␤ test with high AD sensitivity and specificity is of outmost interest. Objective: We evaluated the ability of a commercially available plasma A␤ assay to distinguish AD patients from biomarkerhealthy controls. Method: In a case-control design, we examined plasma samples from 44 AD patients (A + N+) and 49 controls (A-N-) from a memory clinic. AD was diagnosed using a combination of neuropsychological examination, CSF biomarker analysis and brain imaging. Total A␤ 40 and total A␤ 42 in plasma were measured through enzyme-linked immunosorbent assay (ELISA) technology using ABtest40 and ABtest42 test kits (Araclon Biotech Ltd.). Receiver operating characteristic (ROC) analyses with outcome AD were performed, and sensitivity and specificity were calculated.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls

Feinkohl

Schipke

Kruppa

et al. 2020

JAD

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“…Likewise, we cannot exclude that pS129 SNCA in CSF is present in an insoluble fraction or that it is modified in such a way that it no longer becomes recognizable by the antibodies employed in the sandwich assay, and this modifying factor needs to be resistant to the various denaturing treatments tested in this work as well as specific for CSF. This CSF matrix effect, if present, must be specific for pS129 SNCA and cannot generically affect detection of any phospho-protein in CSF as e.g., phosphorylated TAU proteins are readily detected in this matrix (Manniche et al, 2019; Seino et al, 2019). A final possibility is indeed that pS129 SNCA is not present in CSF, at least in the samples we analyzed; and indeed, the detection of pS129 SNCA levels in CSF remains somewhat controversial (Parnetti et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Phospho-S129 Alpha-Synuclein Is Present in Human Plasma but Not in Cerebrospinal Fluid as Determined by an Ultrasensitive Immunoassay

et al. 2019

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Accumulation and aggregation of misfolded alpha-synuclein is believed to be a cause of Parkinson’s disease (PD). Phosphorylation of alpha-synuclein at S129 is known to be associated with the pathological misfolding process, but efforts to investigate the relevance of this post-translational modification for pathology have been frustrated by difficulties in detecting and quantifying it in relevant samples. We report novel, ultrasensitive immunoassays based on single-molecule counting technology, useful for detecting alpha-synuclein and its S129 phosphorylated form in clinical samples in the low pg/ml range. Using human CSF and plasma samples, we find levels of alpha-synuclein comparable to those previously reported. However, while alpha-synuclein phosphorylated on S129 could easily be detected in human plasma, where its detection is extremely sensitive to protein phosphatases, its levels in CSF were undetectable, with a possible influence of a matrix effect. In plasma samples from a small test cohort comprising 5 PD individuals and five age-matched control individuals we find that pS129 alpha-synuclein levels are increased in PD plasma samples, in line with previous reports. We conclude that pS129 alpha-synuclein is not detectable in CSF and recommend the addition of phosphatase inhibitors to plasma samples at the time of collection. Moreover, the findings obtained on the small cohort of clinical plasma samples point to plasma pS129 alpha-synuclein levels as a candidate diagnostic biomarker in PD.

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“…Alterations in cerebrospinal fluid (CSF) composition are reported in aging and neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis 1,2 . In addition to changes in protein levels, large part of the alterations are promoted by the pro-oxidant pathological environment of the CSF which in turn fosters protein oxidative modifications [3][4][5] .…”

mentioning

confidence: 99%

Ceruloplasmin oxidized and deamidated by Parkinson's disease cerebrospinal fluid induces epithelial cells proliferation arrest and apoptosis

Barbariga

Zanardi

Curnis

et al. 2020

Sci Rep

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In Parkinson's disease, the ferroxidase ceruloplasmin (Cp) is oxidized and deamidated by the pathological cerebrospinal fluid (CSF) environment. These modifications promote the gain of integrin binding properties, fostered by the deamidation of two NGR-motifs present in the Cp sequence that convert into the isoDGR-motif. Through isoDGR/integrin binding, the oxidized/deamidated-Cp (Cp-ox/de) mediates cell adhesion and transduces an intracellular signal in epithelial cells that seems to be addressed to regulate cell cycle, proliferation and cytoskeletal re-arrangement. However, the effect fostered on cells by integrins engagement via Cp-ox/de is not known. We found that in HaCaT epithelial cells, the incubation with Cp-ox/de resulted in proliferation inhibition mediated by isoDGR, cell cycle arrest and apoptosis induction. Similar proliferation inhibition was induced by treatment with purified Cp previously incubated in the CSF from Parkinson's disease patients, but not by Cp incubated in the CSF from healthy subjects. In human primary choroid plexus epithelial cells, a possible in vivo target of Cp-ox/de generated in pathological CSFs, we found that Cp-ox/de mediated cell adhesion via isoDGR/integrins binding and transduced an intracellular signal, which resulted in cell proliferation inhibition. Thus, the generation of Cp-ox/de in pathological CSFs and the consequent apoptosis induction of epithelial cells facing the liquor, might represent a novel mechanism that contributes to neurodegeneration.

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Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases

Cited by 29 publications

References 38 publications

Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls

Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls

Phospho-S129 Alpha-Synuclein Is Present in Human Plasma but Not in Cerebrospinal Fluid as Determined by an Ultrasensitive Immunoassay

Ceruloplasmin oxidized and deamidated by Parkinson's disease cerebrospinal fluid induces epithelial cells proliferation arrest and apoptosis

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