Dataset Information

A blood-based signature of cerebrospinal fluid A?_1-42 status.

ABSTRACT: It is increasingly recognized that Alzheimer's disease (AD) exists before dementia is present and that shifts in amyloid beta occur long before clinical symptoms can be detected. Early detection of these molecular changes is a key aspect for the success of interventions aimed at slowing down rates of cognitive decline. Recent evidence indicates that of the two established methods for measuring amyloid, a decrease in cerebrospinal fluid (CSF) amyloid ?_1-42 (A?_1-42) may be an earlier indicator of Alzheimer's disease risk than measures of amyloid obtained from Positron Emission Tomography (PET). However, CSF collection is highly invasive and expensive. In contrast, blood collection is routinely performed, minimally invasive and cheap. In this work, we develop a blood-based signature that can provide a cheap and minimally invasive estimation of an individual's CSF amyloid status using a machine learning approach. We show that a Random Forest model derived from plasma analytes can accurately predict subjects as having abnormal (low) CSF A?_1-42 levels indicative of AD risk (0.84 AUC, 0.78 sensitivity, and 0.73 specificity). Refinement of the modeling indicates that only APOE?4 carrier status and four plasma analytes (CGA, A?_1-42, Eotaxin 3, APOE) are required to achieve a high level of accuracy. Furthermore, we show across an independent validation cohort that individuals with predicted abnormal CSF A?_1-42 levels transitioned to an AD diagnosis over 120 months significantly faster than those with predicted normal CSF A?_1-42 levels and that the resulting model also validates reasonably across PET A?_1-42 status (0.78 AUC). This is the first study to show that a machine learning approach, using plasma protein levels, age and APOE?4 carrier status, is able to predict CSF A?_1-42 status, the earliest risk indicator for AD, with high accuracy.

SUBMITTER: Goudey B

PROVIDER: S-EPMC6409361 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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A blood-based signature of cerebrospinal fluid Aβ1-42 status.

Goudey Benjamin B Fung Bowen J BJ Schieber Christine C Faux Noel G NG

Scientific reports 20190311 1

It is increasingly recognized that Alzheimer's disease (AD) exists before dementia is present and that shifts in amyloid beta occur long before clinical symptoms can be detected. Early detection of these molecular changes is a key aspect for the success of interventions aimed at slowing down rates of cognitive decline. Recent evidence indicates that of the two established methods for measuring amyloid, a decrease in cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42) may be an ...[more]

PMID: 30853713

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Project description:BackgroundTuberculous meningitis (TBM) is an important disease leading to morbidity, disability and mortality that primarily affects children and immune-depressed patients. Specific neuromarkers predicting outcomes, severity and inflammatory response are still lacking. In recent years an increasing number of evidences show a possible role for infective agents in developing neurodegenerative diseases.MethodsWe retrospectively included 13 HIV-negative patients presenting with TBM and we compared them with two control groups: one of patients with a confirmed diagnosis of AD, and one of those with syphilis where lumbar punctures excluded central nervous system involvement. Lumbar punctures were performed for clinical reasons and CSF biomarkers were routinely available: we analyzed blood brain barrier permeability (CSF to serum albumin ratio, "CSAR"), intrathecal IgG synthesis, (CSF to serum IgG ratio), inflammation (neopterin), amyloid deposition (Aβ1-42), neuronal damage (T-tau, P-tau, 14.3.3) and astrocytosis (S-100 β).ResultsTBM patients were 83 % male and 67 % Caucasian with a median age of 51 years (24.5-63.5 IQR). Apart from altered CSAR (median value 18.4, 17.1-30.9 IQR), neopterin (14.3 ng/ml, 9.7-18.8) and IgG ratios (15.4, 7.9-24.9), patients showed very low levels of Aβ1-42 in their CSF (348.5 pg/mL,125-532.2), even lower compared to AD and controls [603 pg/mL (IQR 528-797) and 978 (IQR 789-1178)]. Protein 14.3.3 tested altered in 38.5 % cases. T-tau, P-tau and S100Beta were in the range of normality. Altered low level of Aβ1-42 correlated over time with classical TBM findings and altered neuromarkers.ConclusionsCSF Biomarkers from patients with TBM were compatible with inflammation, blood brain barrier damage and impairment in amyloid-beta metabolism. Amyloid-beta could be tested as a prognostic markers, backing the routine use of available neuromarkers. To our knowledge this is the first case showing such low levels of Aβ1-42 in TBM; its accumulation, drove by neuroinflammation related to infections, can be central in understanding neurodegenerative diseases.

Dataset Information

A blood-based signature of cerebrospinal fluid A?_1-42 status.

Publications

A blood-based signature of cerebrospinal fluid Aβ<sub>1-42</sub> status.

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Dataset Information

A blood-based signature of cerebrospinal fluid A?1-42 status.

Publications

A blood-based signature of cerebrospinal fluid Aβ<sub>1-42</sub> status.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

A blood-based signature of cerebrospinal fluid A?_1-42 status.