Identification of CSF biomarkers for frontotemporal dementia using SELDI-TOF
ABSTRACT This investigation describes the discovery of novel possible cerebrospinal fluid (CSF) biomarkers for frontotemporal dementia (FTD) using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS). Sixteen clinically diagnosed FTD patients and 12 non-demented controls were included in the study. CSF was collected and analyzed for protein expression by SELDI-TOF MS. The samples were analyzed on four different array surfaces using two different energy-absorbing molecules as matrices. In total each sample was subjected to eight different surface/matrix conditions. About 2000 protein peaks (mass/charge ratios) were detected. Forty-two peaks were differentially expressed in FTD (P < 0.01). After exclusion of peaks with low signal-to-noise ratio and/or poor resolution and peaks representing differentially charged proteins, 10 peaks remained, five of which were increased and five decreased in FTD cases compared to controls. Using partial least square discriminant analysis (PLS-DA), the combination of these biomarkers discriminated FTD from non-demented controls with a sensitivity of 94%, a specificity of 83% and an accuracy of 89%. Five of the peaks were purified further and identified by tandem MS as a fragment of neurosecretory protein VGF, transthyretin, S-cysteinylated transthyretin, truncated cystatin C and a fragment of chromogranin B. With use of these potential biomarkers, FTD can be distinguished from control subjects with high accuracy in this pilot study.
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- "VGF was identified in a separate study to be altered in ALS.(Pasinetti et al., 2006) Chromogranin B is a potential marker for FTLD-TDP as it is associated with increased risk for ALS, (Gros-Louis et al., 2009) and cystatin C showed the most promise in being specific to FTLD (or a FTLD subtype) with an opposite direction of change from AD patients.(Ruetschi et al., 2005) As part of a larger targeted proteomic study,(Hu et al., 2010b) we measured CSF levels of 151 proteins in multiplexed immunoassays in 23 patients with autopsy-confirmed FTLD-TDP or FTLD- Tau, along with 80 living patients with a clinical syndrome suggestive of underlying FTLD pathology (bv-FTD, PPA, CBS) whose CSF levels of AD-biomarke"
ABSTRACT: Neuronal and glial changes associated with tau, TAR DNA binding protein of ∼43 kDa (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice.Progress in Neurobiology 04/2011; 95(4):636-48. DOI:10.1016/j.pneurobio.2011.04.012 · 10.30 Impact Factor
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- "In addition: (1) VGF 23– 62 was consistently increased in two independent groups of schizophrenic patients (ϳ40%); (2) the increase was confirmed in a small group (nϭ5) of post mortem brains by western blot; (3) VGF 23– 62 was also increased in a small group of depressed patients (nϭ16), but not in obsessive compulsive disorder (nϭ5) or Alzheimer's patients (nϭ10), suggesting that it could be associated with underlying mechanisms of both schizophrenia and depression, and that the diagnosis of schizophrenia would require an association of several disease biomarkers; (4) the VGF 26 – 62 fragment (truncated by three N-terminal aa when compared to the 23– 62 fragment) was identified in the CSF, but did not discriminate between schizophrenic and normal patients. Interestingly the VGF 26 – 62 fragment is decreased in frontotemporal dementia patients (see above, Rüetschi et al. (2005)). A later report by the same group showed a similar increase in VGF 23-62 fragment in a set of patients prodromal for psychosis (nϭ24), a fraction (29%) of which became schizophrenic during the 3 years follow up (Huang et al., 2007). "
ABSTRACT: The identification of biomarkers represents a fundamental medical advance that can lead to an improved understanding of disease pathogenesis, and holds the potential to define surrogate diagnostic and prognostic endpoints. Because of the inherent difficulties in assessing brain function in patients and objectively identifying neurological and cognitive/emotional symptoms, future application of biomarkers to neurological and psychiatric disorders is extremely desirable. This article discusses the biomarker potential of the granin family, a group of acidic proteins present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: chromogranin A (CgA), CgB, Secretogranin II (SgII), SgIII, HISL-19 antigen, 7B2, NESP55, VGF and ProSAAS. Their relative abundance, functional significance, and secretion into the cerebrospinal fluid (CSF), saliva, and the general circulation have made granins tractable targets as biomarkers for many diseases of neuronal and endocrine origin, recently impacting diagnosis of a number of neurological and psychiatric disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. Although research has not yet validated the clinical utility of granins as surrogate endpoints for the progression or treatment of neurological or psychiatric disease, a growing body of experimental evidence indicates that the use of granins as biomarkers might be of great potential clinical interest. Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational effectiveness of this family of proteins in disease diagnosis and drug discovery.Neuroscience 09/2010; 170(1):289-97. DOI:10.1016/j.neuroscience.2010.06.057 · 3.33 Impact Factor
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- "CgB stimulates neurite outgrowth (Chen et al. 1992) and is the precursor of several peptides with unknown functions, some of which have been extracted from human tumor tissue (Stridsberg et al. 2005). The CgB-derived 6252 Da biomarker analyzed in this study was earlier described as a biomarker decreased in frontotemporal dementia (Rüetschi et al. 2005). This biomarker is related to GAWK-peptide (CgB amino acids 420–493), which has been extracted from normal human pituitary, and is increased in endocrine tumor tissue and in plasma of patients with these tumors (Benjannet et al. 1985; Sekiya et al. 1989; Stridsberg et al. 2005). "
ABSTRACT: Novel biomarkers for multiple sclerosis (MS) could improve diagnosis and provide clues to pathogenesis. In this study surface-enhanced laser desorption/ionization time-of-flight mass spectrometry was used to analyze protein expression in CSF from 46 MS patients, 46 healthy siblings to the patients, and 50 unrelated healthy controls. Twenty-four proteins in the mass range 2-10 kDa were expressed at significantly different levels (p < 0.01) in a robust manner when comparing the three groups. Identities of three proteins were determined using biochemical purification followed by tandem mass spectrometric analysis. Immunoprecipitation experiments confirmed the identities for two peptides derived from chromogranin B (m/z 6252) and from secretogranin II (m/z 3679). These peptides were all decreased in MS when compared with siblings or controls. Radioimmunoassays specific for each peptide confirmed these differences. The lowered concentrations did not correlate to the axonal damage marker neurofilament light protein and may thus reflect functional changes rather than neurodegeneration. Further studies will investigate the involvement of these peptides in MS pathogenesis.Journal of Neurochemistry 12/2007; 103(5):1932-9. DOI:10.1111/j.1471-4159.2007.04985.x · 4.24 Impact Factor