Biomarkers for the Diagnosis of ALS

Abstract

Methods for determining the onset of ALS in a subject are provided. One method includes analyzing a sample obtained from the subject for the presence or amount of one or more biomarkers indicative of ALS. In a preferred embodiment, the biomarkers are one or more of the following: C-reactive protein (CRP), cystatin c, plasminogen, complement C3, CysGly-transthyretin, and phosphorylated neurofilament heavy chain (pNFH). The sample is typically cerebral spinal fluid (CSF). The levels or concentrations of the biomarkers can be used to determine the onset of ALS, monitor the progression of ALS, or monitor the progression of a treatment for ALS.

1 . A method of selecting a subject for treatment for amyotrophic lateral sclerosis (ALS) comprising
 a) measuring the concentration of the phosphorylated neurofilament heavy chain (pNFH) in a cerebrospinal fluid sample obtained from the subject;   b) measuring the concentration of complement C3 in a cerebrospinal fluid sample obtained from the subject; and   c) selecting the subject for treatment of ALS if at least one of the following is true;
 i) the concentration of pNFH is equal to or greater than 1.366 ng/ml and the subject is female; 
 ii) the concentration of pNFH is equal to or greater than 1.366 ng/ml, the concentration of complement C3 is equal to or greater than 1.197 μg/ml and the subject is male; 
 iii) the concentration of pNFH is 0.645-1.366 ng/ml, the concentration of complement C3 is 1.005-4.475 μg/ml and the subject is female; or 
   iv) the concentration of pNFH is equal to or greater than 1.366 ng/ml and the concentration of complement C3 is 1.005-4.475 μg/ml.   
     
     
         2 . The method of  claim 1 , wherein the subject is a human. 
     
     
         3 . The method of  claim 1 , further comprising the step of administering a treatment to the subject. 
     
     
         4 . The method of  claim 3  wherein the subject is treated with Riluzole. 
     
     
         5 . The method of  claim 1  wherein the concentrations of pNFH and complement C3 are measured by immunoassay or mass spectrometric measures. 
     
     
         6 . The method of  claim 5  wherein the concentrations of pNFH and complement C3 are measured by ELISA. 
     
     
         7 . The method of  claim 5  wherein the concentrations of pNFH and complement C3 are measured by mass spectrometric measures including Surface Enhanced Laser Dissociation/Ionization Time-of-Flight Mass Spectroscopy (SELDI-TOF-MS) or Liquid Chromatography-Mass Spectroscopy/Mass Spectroscopy (LS-MS/MS). 
     
     
         8 . A method of selecting a subject for treatment for amyotrophic lateral sclerosis (ALS) comprising
 a) measuring the concentration of the phosphorylated neurofilament heavy chain (pNFH) in a cerebrospinal fluid sample obtained from the subject;   b) measuring the concentration of complement C3 in a cerebrospinal fluid sample obtained from the subject;   c) measuring the concentration of total cerebrospinal fluid protein (CSF) and;   d) selecting the subject for treatment of ALS if at least one of the following is true;
 i) the total CSF protein concentration is 569-714 μg/ml and the concentration of pNFH is equal to or greater than 1.366 ng/ml; or 
 ii) the concentration or level of total CSF protein is less than 719 μg/ml, the concentration of complement C3 is not between 1.005-4.475 and the concentration of pNFH is equal to or greater than 0.645 ng/ml. 
   
     
     
         9 . The method of  claim 8 , wherein the subject is a human. 
     
     
         10 . The method of  claim 8 , further comprising the step of administering a treatment to the subject. 
     
     
         11 . The method of  claim 10  wherein the subject is treated with Riluzole. 
     
     
         12 . The method of  claim 8  wherein the concentrations of pNFH, complement C3 and total CSF protein are measured by immunoassay or mass spectrometric measures. 
     
     
         13 . The method of  claim 12  wherein the concentrations of pNFH, complement C3 and total CSF protein are measured by ELISA. 
     
     
         14 . The method of  claim 12  wherein the concentrations of pNFH, complement C3 and total CSF protein are measured by mass spectrometric measures including Surface Enhanced Laser Dissociation/Ionization Time-of-Flight Mass Spectroscopy (SELDI-TOF-MS) or Liquid Chromatography-Mass Spectroscopy/Mass Spectroscopy (LS-MS/MS). 
     
     
         15 . A method of selecting a subject for treatment for amyotrophic lateral sclerosis (ALS) comprising
 a) measuring the concentration of the phosphorylated neurofilament heavy chain (pNFH) in a cerebrospinal fluid sample obtained from the subject;   b) measuring the concentration of cystatin C in a cerebrospinal fluid sample obtained from the subject;   c) selecting the subject for treatment of ALS if the concentration of pNFH is equal to or greater than 0.75 ng/ml and the concentration of cystatin C is equal to or less than 2.0 μg/ml.   
     
     
         16 . The method of  claim 15 , further comprising the step of administering a treatment to the subject. 
     
     
         17 . The method of  claim 16  wherein the drug is Riluzole. 
     
     
         18 . The method of  claim 15  wherein the concentrations of pNFH and cystatin C are measured by immunoassay or mass spectrometric measures. 
     
     
         19 . The method of  claim 18  wherein the concentrations of pNFH and cystatin C are measured by ELISA. 
     
     
         20 . The method of  claim 18  wherein the concentrations of pNFH and cystatin C are measured by mass spectrometric measures including Surface Enhanced Laser Dissociation/Ionization Time-of-Flight Mass Spectroscopy (SELDI-TOF-MS) or Liquid Chromatography-Mass Spectroscopy/Mass Spectroscopy (LS-MS/MS).