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  • 1. Review PaperEarly detection of Amyotrophic Lateral Sclerosis using Proteomic and Metabolomic studiesto identify biomarkersTorres Juan C.UPR Cayey, Department of Biology, PR.AbstractAmyotrophic Lateral Sclerosis (ALS)is a neurodegenerative disease that affects the motorneurons. It has no cure, but treatments are being made that extend life expectancy. Biomarkers is atopic that is associated with the early diagnosis of diseases. Scientists are trying to findbiomarkers that could help in the early diagnosis and prognosis of ALS, and for the utilizationinroutine patient checkup. Two fields of science that are studying specific biomarkers for earlydiagnosis in ALS are Proteomics and Metabolomics, with progress in finding biomarkers for ALS.They utilized different techniques to find biomarkers using the same sample collection fromcerebrospinal fluid or plasma. The results for the search of biomarker for ALS using metabolomicsshowed that 17 metabolites could be identifiedas possible biomarkers while only threebiomarkers for proteomics were identified. Of all the biomarker related to ALS,cystatin C is theclosest specific biomarker that scientist have for the moment. Science found some biomarkersinboth of these areas, but those specific biomarkers have still to go through validation and morestudies need to be performed.Introduction months in some patients to decades forAmyotrophic lateral sclerosis (ALS) is a approximately 5% of the patients diagnosedprogressive neurodegenerative disease with the disease(Gordon 2011).This is theassociated with a life expectancy of third most commonneurodegenerativeapproximately 3 years after symptom onset, disease after Alzheimer and Parkinsonbut the range of survival extends from a few disease with a prevalence of 4-6 per 100.000
  • 2. individuals and a mean age of onset of about chemical tests to exclude other conditions56 years. As a motor neuron disease, ALS is with similar symptoms. The presentcharacterized by the selective progressive protocols for diagnosis lead to delays anddegeneration of motor neurons in the brain, may result in misdiagnosis (Wuolikainenbrainstem and spinal cord (Süssmuthet al. etal. 2009). Biomarkers also hold promise to2008). Unfortunately, there is only one drug monitor disease progression and to stratifycurrently approved by the FDA to treat ALS, patient populations for use in clinical trials.which is riluzole, and this therapy increases Biomarkers that monitor disease progressionlife span by just two to three months on would aid in the design and execution ofaverage (Wilson et al. 2010). There is a need human clinical trials and would providein finding an early diagnosis of this disease; novel targets for future drug therapiesmore scientists are looking for biomarkers Prognostic biomarkers that predict patientthat help give an early prognosis of the survival would also aid in the design ofdisease. Biomarkers in human blood or clinical trials (Wilson etal. 2010). Proteomicscerebrospinal fluid (CSF) are urgently profiling helps to find biomarkers in theneeded for diagnosis,evaluation, and identification of ALS specific proteineffectivetreatment in ALS and other biomarkers that may provide insight into theneurodegenerative diseases (Wuolikainen et nature of the degenerative process.al. 2009). Two fields in science, Proteomics Additionally, biomarkersfound throughand Metabolomics, are searching for more proteomics profiling may be useful both inspecific biomarkers for ALS. At the present the diagnosis of ALS and in monitoring thetime, no verified specific biomarkers exist for effect of the therapeutic interventionsALS and diagnosis is currently made (Ranganathanetal. 2005). On the other hand,following clinical examination, metabolomics offers unique possibilities toneurophysiological tests and various simple screen for molecular biomarkers in human
  • 3. biofluids and tissues (Wuolikainen etal. point tocystatin C as a leap forward in the2009). In comparison, proteomics has right direction.advanced more in identifying specific Metabolomic Studies on ALS researchbiomarkers than Metabolomics. They both Metabolomics is a newborn cousin touse cerebrospinal fluid and plasma for their genomics and proteomics. (I wouldexperimental trials. From proteomic profiling eliminate this sentence. It is too much tothree biomarkers were identified that digest and loses me as a reader.)decreased transthyretin, cystatin Cor Metabolomics is increasingly being used in aincreased carboxy-terminal fragment of variety of health applications includingneuroendocrine protein 7B2in ALS CSF pharmacology,pre-clinical drug trials,(cerebrospinal fluid)(Ranganathanet al. toxicology, transplant monitoring, newborn2005). Cystatin C is a possible candidate for screening and clinical chemistry. Thebiomarker that has been extensively growing field called Metabolomics detectsresearched.It is a widely expressed cysteine and quantifies the low molecular weight ofprotease inhibitor that is approximately five molecules, known as metabolites, producedtimes more abundant in CSF than in by active, living cellsunder differentplasma.The challenge is to make cystatin C conditions and times in their life cycles.clinically useful as a diagnostic biomarker. NMR (nuclear magnetic resonance) isTo do this it must also be able to differentiate playing an important role in metabolomicsbetween ALS patients and individuals with because of its ability to observe mixtures ofneurologic diseases that closely resemble small molecules in living cells or in cellALS, or ALS ‘‘mimic diseases.’’ (Wilson et extracts (Tyagi et al. 2010). Metabolomics isal. 2010). In any event, these findings concerned with the quantification andcontribute to the advancement of science, and identification of a large number of low molecular compounds in biological samples.
  • 4. For example, by means of multiple sample (Blasco et al. 2010). A studydone bycomparisons, single metabolites or patterns Christian R. Andres and colleaguesalso usedof metabolites are extracted to see if their metabolomics to identify certain biomarkers.concentration is significantly altered in The aim of thisstudy was to analyze the CSFrelation tothe onset and progression of a of patients with ALS by 1H NMR (Nuclearspecific diseaseor the response to a specific Magnetic Resonance) spectroscopy in ordertreatment (Wuolikainen et al.2009). to identify biomarkers in the early stages ofRecently, high-throughput techniques such as the disease, and to evaluate the biochemicalmetabolomics have been used to evaluate a factors involved in ALS. Their resultscombination of markers in patients with showed 17 metabolites that could be possibleneurological diseases, such as ALS. biomarkers for ALS. That same studyMetabolomic studies have been performed focused on the NMR profile, but they arevia different analytical methods such as high aware that accuracy of early diagnosis ofperformance liquid chromatography followed ALS will depend on a combination of severalby electrochemical detection approaches likeimaging, electrophysiologicalorhighresolution 1H NMR spectroscopy. and biological markers (Blasco et al.2010).NMR spectroscopy appears to be cost- Further studies with larger numbers ofeffective, useful in routine care, and patients and controls, including other motorscreening. Different kinds of biological fluids neuron diseases, will be crucial to validatehave been screened, but this researcher also this model and to assure its place in routineconfirms that CSF may have the highest yield practice (Blasco et al.2010). The conclusionof biomarkers in ALS. Some of the reasons of that study is that CSF screening by NMRare because of its direct contact with the spectroscopy could be a useful, simple andbrain, its accessibility, and its dynamic low cost tool to improve the early diagnosischanges with the cerebral environment of ALS. The results indicate a perturbation of
  • 5. glucose metabolism, and the need to further both in the diagnosis of this disease and inexplore cerebral energetic metabolism. monitoring the response of the degenerative process to therapeutic interventions.Proteomic studies on ALS research Proteomic analyses have been used toProteomics encompasses the study of uncover biomarkers in other CNS disordersexpressed proteins, including identification and neurodegenerative diseases such asand elucidation of the structure-function multiple sclerosis, schizophrenia,interrelationships that define healthy and Alzheimer’s disease, and HIV-1 associateddisease conditions (Wright and Semmes cognitive impairment (Ranganathanetal.2003). In ALS, changes in protein 2005). Robert Bowser usedproteomic profilecomposition of the cerebrospinal fluid (CSF) of CSF from recently diagnosed ALSor serum may denote corresponding patients and control subjects using surface-alterations in protein expression, post- enhanced laser desorption/ionization time-of-translational modifications or turnover within flight mass spectrometry (SELDI-TOF-MS)the tissue of the central nervous system. for his study to find specific biomarkers.Because CSF contains proteins and protein Three biomarkers were identified thatcouldfragments released from ALS-affected be possible biomarkers which areneurons and glia, it seems likely that profiles transthyretin, cystatin C and carboxy-of CSF proteins may serve as biomarkers for terminal fragment of neuroendocrine proteinthe process of motor neuron degeneration in 7B2in ALS CSF. The cysteine proteasethe spinal cord in this ALS. Indeed, the inhibitor cystatin C has recently gainedidentification of ALS specific protein interest as a candidate diagnostic biomarkerbiomarkers may provide insight into the for ALS, but further studies are required tonature of the degenerative process. fully characterize its biomarker utility.Additionally, such biomarkers may be useful Cystatin C levels in ALS patients were
  • 6. significantly elevated in plasma and reduced Proteomics and Metabolomics are newin CSF compared to healthy controls.Cystatin studies that can be applied for an earlyC is also linked to ALS histopathologically, detection of amyotrophic lateral sclerosis.as it is one of only two known proteins that These advances are great, but there is stilllocalize to Bunina bodies. Bunina bodiesare progress to be made, the results in thosesmall intraneuronal inclusions specific to studies still require validation. Both of theseALS. Plasma cystatin C has been extensively areas of research have more pros than conscharacterized as a peripheral biomarker for and are an improvement towards finding thekidney function and as a prognostic indicator cause and a cure for ALS then most scientistof the risk of morbidity and mortality relating imagine. These studies also bring newto cardiovascular disease. However, blood- techniques and forms to detect biomarkersborne levels of cystatin C have not been for an early prognosis of ALS. Proteomicsevaluated as a biomarker candidate for and Metabolomics have helped in other typeneurologic disorders such as ALS. (Wilson et of diseases such as multiple sclerosis,al.2010). schizophrenia, Alzheimer’s disease, and HIV-1 associated cognitive impairment.Conclusion Also, they have been recently helpful in theAmyotrophic lateral sclerosis is a disease that area of cancer for early prognosis. Inaffects a small portion of the population of conclusion, additional studies need to bethe United States. A cure for the disease has conducted so that these techniquescouldnot been found and the struggle in finding eventually be performedin a patient’s routinenew therapies or techniques that extend the checkup.life span of the patient are being looked at.
  • 7. ReferenceBlasco H, Corcia P, Moreau C, Veau S, Fournier C, Vourc’h P, Emond Patrick, Gordon P, Pradat PF, Praline J, Devos D, Desbarats L and Andres CR. 2010. H-NMR-Based Metabolomic Profiling of CSF in Early Amyotrophic Lateral Sclerosis. Plos One. 5(10):e13223Gordon P. Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis and Management. 2011. CNS Drugs. 25(1):1-16Ranganathan S, Williams E, Ganchev P, Gopalakrishnan V, Lacomis D, Urbinelli à L, Newhall K, Cudkowicz ME, Brown Jr. RH and Bowser R. 2005. Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis. Journal of Neurochemestry. 95:1461– 1471Süssmuth S, Brettschneider J, Ludolph A and Tumani Hayrettin.Biochemical Markers in CSF of ALS Patients. 2008. Current Medical Chemistry. 15:1788-1801Tyagi S, Raghvendra, Singh U, Kalra T and Munjal K. Applications of metabolomics - a systematic study of the unique chemical fingerprints: an overview. 2010. International Journal of Pharmaceutical Sciences Review and Research. 3(1):83-86Wilson ME, Boumaza I, Lacomis D and Bowser R. Cystatin C: A Candidate Biomarker for Amyotrophic Lateral Sclerosis. 2010. Plos One. 5(12):e15133.Wright G and Semmes O. Proteomics in Health and Disease. 2003. Journal of Biomedicine and Biotechnology. 4:215-216Wuolikainen A, Moritz T, Marklund SL, Antti H, Munch P. Disease-Related Changes in the Cerebrospinal Fluid Metabolome in Amyotrophic Lateral Sclerosis Detected by GC/TOFMS. 2011. Plos One. 6(4):e17947Wuolikainen A, Hedenstro M, Moritz T, Marklund SL, Antti H and Andersen PM. Optimization of procedures for collecting and storing of CSF for studying the metabolome in ALS. 2009. The World Federation Of Neurology Research Group On Motor Neuron Diseases. 10(4):229- 236