Article

Biomarker discovery for Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease

Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
Acta Neuropathologica (Impact Factor: 10.76). 09/2010; 120(3):385-99. DOI: 10.1007/s00401-010-0723-9
Source: PubMed

ABSTRACT Ante-mortem diagnosis of neurodegenerative disorders based on clinical features alone is associated with variable sensitivity and specificity, and biomarkers can potentially improve the accuracy of clinical diagnosis. In patients suspected of having Alzheimer's disease (AD), alterations in cerebrospinal fluid (CSF) biomarkers that reflect the neuropathologic changes of AD strongly support the diagnosis, although there is a trade-off between sensitivity and specificity due to similar changes in cognitively healthy subjects. Here, we review the current approaches in using CSF AD biomarkers (total tau, p-tau(181), and Abeta42) to predict the presence of AD pathology, and our recent work using multi-analyte profiling to derive novel biomarkers for biofluid-based AD diagnosis. We also review our use of the multi-analyte profiling strategy to identify novel biomarkers that can distinguish between subtypes of frontotemporal lobar degeneration, and those at risk of developing cognitive impairment in Parkinson's disease. Multi-analyte profiling is a powerful tool for biomarker discovery in complex neurodegenerative disorders, and analytes associated with one or more diseases may shed light on relevant biological pathways and potential targets for intervention.

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Available from: Holly D Soares, Jul 02, 2014
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    • "Analyte stability over years of storage, even at −80 °C, needs to be determined for each biomarker of interest [35], or has – at least – to be considered during data analyses (in regression models) as an indirect , independent variable covering the storage duration for each individual sample. The longitudinal design of the DONALD Study along with its long-term urine biobanking allowed us to address this important methodological stability question directly and specifically. "
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    ABSTRACT: To examine the long-term stability and validity of analyte concentrations of 21 clinical biochemistry parameters in 24-h urine samples stored for 12 or 15yr at -22°C and preservative free.
    Clinical Biochemistry 09/2014; 47(18). DOI:10.1016/j.clinbiochem.2014.09.009 · 2.28 Impact Factor
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    • "For example, the neuroleptic drugs that are often used to treat the psychiatric symptoms in AD can be detrimental to DLB patients. Because of the overlapping pathologies between these two disorders, the standard CSF biomarkers for AD (Aβ1–42, T-tau, and P-tau) do not readily discriminate between them [41-44]. Future large clinical studies are needed to evaluate whether CSF α-synuclein oligomers, when combined with biomarkers for AD, could increase the diagnostic precision in distinguishing dementia patients with AD from those patients with DLB and PDD. "
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    ABSTRACT: Introduction The objective was to study whether α-synuclein oligomers are altered in the cerebrospinal fluid (CSF) of patients with dementia, including Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD), compared with age-matched controls. Methods In total, 247 CSF samples were assessed in this study, including 71 patients with DLB, 30 patients with PDD, 48 patients with AD, and 98 healthy age-matched controls. Both total and oligomeric α-synuclein levels were evaluated by using well-established immunoassays. Results The levels of α-synuclein oligomers in the CSF were increased in patients with PDD compared with the controls (P < 0.05), but not in patients with DLB compared with controls. Interestingly, the levels of α-synuclein oligomers in the CSF were also significantly higher in patients with PDD (P < 0.01) and DLB (P < 0.05) compared with patients with AD. The levels of CSF α-synuclein oligomers and the ratio of oligomeric/total-α-synuclein could distinguish DLB or PDD patients from AD patients, with areas under the curves (AUCs) of 0.64 and 0.75, respectively. In addition, total-α-synuclein alone could distinguish DLB or PDD patients from AD patients, with an AUC of 0.80. Conclusions The levels of α-synuclein oligomers were increased in the CSF from α-synucleinopathy patients with dementia compared with AD cases.
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    • "Despite significant advances in neuroradiological techniques and the emergence of possible biomarkers [1,2] the gold standard for diagnosis of neurodegenerative diseases remains the histological examination of post mortem brain tissue on the background of clinical evaluation. As new targeted therapies emerge the accurate diagnosis of neurodegenerative diseases in life may well become even more important. "
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