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Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-?(1-42) and ? proteins as Alzheimer disease biomarkers.

ABSTRACT: BACKGROUND:Over the past 2 decades, clinical studies have provided evidence that cerebrospinal fluid (CSF) amyloid ?(1-42) (A?(1-42)), total ? (t-?), and ? phosphorylated at Thr181 (p-?(181)) are reliable biochemical markers of Alzheimer disease (AD) neuropathology. CONTENT:In this review, we summarize the clinical performance and describe the major challenges for the analytical performance of the most widely used immunoassay platforms [based on ELISA or microbead-based multianalyte profiling (xMAP) technology] for the measurement of CSF AD biomarkers (A?(1-42), t-?, and p-?(181)). With foundational immunoassay data providing the diagnostic and prognostic values of CSF AD biomarkers, the newly revised criteria for the diagnosis of AD include CSF AD biomarkers for use in research settings. In addition, it has been suggested that the selection of AD patients at the predementia stage by use of CSF AD biomarkers can improve the statistical power of clinical trial design. Owing to the lack of a replenishable and commutable human CSF-based standardized reference material (SRM) and significant differences across different immunoassay platforms, the diagnostic-prognostic cutpoints of CSF AD biomarker concentrations are not universal at this time. These challenges can be effectively met in the future, however, through collaborative ongoing standardization efforts to minimize the sources of analytical variability and to develop reference methods and SRMs. SUMMARY:Measurements of CSF A?(1-42), t-?, and p-?(181) with analytically qualified immunoassays reliably reflect the neuropathologic hallmarks of AD in patients at the early predementia stage of the disease and even in presymptomatic patients. Thus these CSF biomarker tests are useful for early diagnosis of AD, prediction of disease progression, and efficient design of drug intervention clinical trials.

SUBMITTER: Kang JH

PROVIDER: S-EPMC4159709 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β(1-42) and τ proteins as Alzheimer disease biomarkers.

Kang Ju-Hee JH Korecka Magdalena M Toledo Jon B JB Trojanowski John Q JQ Shaw Leslie M LM

Clinical chemistry 20130321 6

<h4>Background</h4>Over the past 2 decades, clinical studies have provided evidence that cerebrospinal fluid (CSF) amyloid β(1-42) (Aβ(1-42)), total τ (t-τ), and τ phosphorylated at Thr181 (p-τ(181)) are reliable biochemical markers of Alzheimer disease (AD) neuropathology.<h4>Content</h4>In this review, we summarize the clinical performance and describe the major challenges for the analytical performance of the most widely used immunoassay platforms [based on ELISA or microbead-based multianaly ...[more]

PMID: 23519967

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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.

Project description:Introduction: Amyloid beta 1-43 (A?43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer's disease pathology possibly different from that of amyloid beta 1-42 (A?42). Cerebrospinal fluid (CSF) A?43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer's disease. However, the relationship between CSF A?43 and established imaging biomarkers of Alzheimer's disease has never been assessed. Materials and Methods: In this observational study, CSF A?43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent 18F-Flutemetamol PET. Seventy-eight subjects were assessed with 18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging. Results: Cerebrospinal fluid A?43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF A?43 between subjects with 18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml, n = 27) and positive (15 pg/ml, n = 9), p < 0.001. Both CSF A?43 and A?42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF A?43 average rho -0.73, A?42 -0.74. Both CSF A? peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF A?42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF A?43/42 and imaging biomarkers were significantly different for the two A? peptides when controlling for multiple testing. Conclusion: Cerebrospinal fluid A?43 appears to be strongly correlated with cerebral amyloid deposits in the same way as A?42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF A?43 performs better than the classical CSF biomarker A?42 for distinguishing SCD and MCI.

Dataset Information

Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-?(1-42) and ? proteins as Alzheimer disease biomarkers.

Publications

Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β(1-42) and τ proteins as Alzheimer disease biomarkers.

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