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Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay

Heywood, W. E. (författare)
Galimberti, D. (författare)
Bliss, E. (författare)
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Sirka, E. (författare)
Paterson, R. W. (författare)
Magdalinou, N. K. (författare)
Carecchio, M. (författare)
Reid, E. (författare)
Heslegrave, A. (författare)
Fenoglio, C. (författare)
Scarpini, E. (författare)
Schott, J. M. (författare)
Fox, N. C. (författare)
Hardy, J. (författare)
Bahtia, K. (författare)
Heales, S. (författare)
Sebire, N. J. (författare)
Zetterberg, Henrik, 1973 (författare)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Mills, K. (författare)
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 (creator_code:org_t)
 
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2015
2015
Engelska.
Ingår i: Molecular Neurodegeneration. - 1750-1326. ; 10
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Background: Currently there are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. Lewy Body Dementia (LBD) is considered an under diagnosed form of dementia for which markers are needed to discriminate LBD from other forms of dementia such as Alzheimer's Disease (AD). This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD. Using this technology we identified several potential novel markers for LBD. These were then combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM-LC-MS/MS assay. This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer's and Parkinson's disease (PD). Results: Thirty eight proteins showed significantly (p < 0.05) altered expression in LBD CSF by proteomic profiling. The targeted MRM-LC-MS/MS assay revealed 4 proteins that were specific for the identification of AD from LBD: ectonucleotide pyrophosphatase/phosphodiesterase 2 (p < 0.0001), lysosome-associated membrane protein 1 (p < 0.0001), pro-orexin (p < 0.0017) and transthyretin (p < 0.0001). Nineteen proteins were elevated significantly in both AD and LBD versus the control group of which 4 proteins are novel (malate dehydrogenase 1, serum amyloid A4, GM2-activator protein, and prosaposin). Protein-DJ1 was only elevated significantly in the PD group and not in either LBD or AD samples. Correlations with Alzheimer-associated amyloid beta-42 levels, determined by ELISA, were observed for transthyretin, GM2 activator protein and IGF2 in the AD disease group (r(2) >= 0.39, p <= 0.012). Cystatin C, ubiquitin and osteopontin showed a strong significant linear relationship (r(2) >= 0.4, p <= 0.03) with phosphorylated-tau levels in all groups, whilst malate dehydrogenase and apolipoprotein E demonstrated a linear relationship with phosphorylated-tau and total-tau levels in only AD and LBD disease groups. Conclusions: Using proteomics we have identified several potential and novel markers of neurodegeneration and subsequently validated them using a rapid, multiplexed mass spectral test. This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between AD from LBD.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

Lewy body dementia
Alzheimer's disease
Targeted proteomics
CSF biomarker
ONSET ALZHEIMERS-DISEASE
CEREBROSPINAL-FLUID
MASS-SPECTROMETRY
PARKINSONS-DISEASE
CLINICAL-DIAGNOSIS
PLASMA BIOMARKERS
COGNITIVE
DECLINE
ALPHA-SYNUCLEIN
TAU-PROTEIN
DEMENTIA
Neurosciences
KHANN G
1984
NEUROLOGY
V34
P939
KEITH IG
1994
NEUROLOGY
V44
P872

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