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


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: Objective: 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 15 yr at -22°C and preservative free. Design and methods: Healthy children's 24-h urine samples in which the respective analytes had been measured shortly after sample collection (baseline) were reanalyzed. Second measurement was performed after 12 yr (organic acids) and 15 yr (creatinine, urea, osmolality, iodine, nitrogen, anions, cations, acid-base parameters) with the same analytical methodology. Paired comparisons and correlations between the baseline and repeated measurements were done. Recovery rates were calculated. Results: More than half of the analytes (creatinine, urea, iodine, nitrogen, sodium, potassium, magnesium, calcium, ammonium, bicarbonate, citric & uric acid) showed measurement values after >10 yr of storage not significantly different from baseline. 15 of the 21 parameters were highly correlated (r=0.99) between baseline and second measurement. Poorest correlation was r=0.77 for oxalate. Recovery ranged from 73% (oxalate) to 105% (phosphate). Conclusion: Our results suggest high long-term stability and measurement validity for numerous clinical chemistry parameters stored at -22°C without addition of any urine preservative. Prospective storage of urine aliquots at -22°C for periods even exceeding 10 yr, appears to be an acceptable and valid tool in epidemiological settings for later quantification of several urine analytes.
    Full-text · Article · Sep 2014 · Clinical Biochemistry
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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.
    Full-text · Article · May 2014 · Alzheimer's Research and Therapy
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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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    ABSTRACT: In theory, cerebral biopsies could provide the diagnosis in a significant proportion of patients with neurodegenerative diseases, however, there are considerable ethical barriers. Previous series of cerebral biopsies have shown variable diagnostic accuracy but have understandably suffered because of lack of post-mortem tissue with which to compare the diagnosis. To determine the accuracy of such biopsies in neurodegenerative disease we took small biopsy-sized samples of predominantly fresh post-mortem brain tissue from frontal and temporal lobes in 62 cases. These were processed as for a biopsy and stained for H&E, p62, tau, Aβ, α-synuclein, and TDP-43. The sections were assessed blind by 3 neuropathologists and the results compared with the final post-mortem diagnosis. The agreement and sensitivity in most cases was good especially: controls; Alzheimer's disease (AD); multiple system atrophy (MSA); frontotemporal lobar degeneration with TDP-43 positive inclusions and/or motor neurone disease (FTLD-TDP/MND); Huntington's disease (HD); corticobasal degeneration (CBD) / microtubular associated protein tau mutation cases with CBD-like features (CBD/MAPT); and combined AD- Dementia with Lewy Bodies (AD-DLB) where the sensitivity on assessing both brain regions varied between 75-100%. There was poor sensitivity for progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) (both 0%), but moderate sensitivity for pure DLB (60%). The temporal lobe assessment was marginally more accurate than the frontal lobe but these were only slightly worse than both combined. The study shows that with certain caveats the cerebral biopsy in life should be a viable method of accurately diagnosing many neurodegenerative diseases.
    Full-text · Article · Aug 2013
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