Methods for measuring the metabolism of neurally derived biomolecules in vivo

Abstract

The present invention relates to methods of diagnosing, monitoring, and assessing treatment effects for neurological and neurodegenerative diseases and disorders, such as Alzheimer's Disease, early in the course of clinical disease or prior to the onset of brain damage and clinical symptoms. Methods of measuring the in vivo metabolism of biomolecules produced in the CNS in a subject are provided.

1 . A kit for diagnosing or monitoring the progression or treatment of a neurological or neurodegenerative disease in a subject, the kit comprising:
 (a) a labeled amino acid;   (b) means for administering the labeled amino acid to the subject, whereby the labeled amino acid is capable of crossing the blood brain barrier and incorporating into and labeling a protein as the protein is being synthesized in the central nervous system of the subject;   (c) means for obtaining a biological sample at regular time intervals from the subject, the biological sample comprising a labeled protein fraction and an unlabeled protein fraction; and   (d) instructions for detecting and determining the ratio of labeled to unlabeled protein over time so that a metabolic index may be calculated, whereby the metabolic index may be compared to the metabolic index of a normal, healthy individual or compared to a metabolic index from the same subject generated at an earlier time, wherein the protein is selected from the group consisting of amyloid-beta, apolipoprotein E, apolipoprotein J, synuclein, soluble amyloid precursor protein, Tau, alpha-2 macroglobulin, S100B, myelin basic protein, an interleukin, and TNF.   
     
     
         2 . The kit of  claim 1 , wherein the neurological or neurodegenerative disease is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, stroke, frontal temporal dementias (FTDs), Huntington's Disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), aging-related disorders and dementias, Multiple Sclerosis, Prion Diseases, Lewy Body Disease, and Amyotrophic Lateral Sclerosis. 
     
     
         3 . The kit of  claim 1 , wherein the protein synthesized is from a neuronal cell, glial cell, or other cell in the central nervous system. 
     
     
         4 . The kit of  claim 1 , wherein the labeled amino acid has a radioactive or a non-radioactive atom. 
     
     
         5 . The kit of  claim 4 , wherein the non-radioactive atom is selected from the group consisting of 2H, 13C, 15N, 17O, 18O, 33S, 34S, and 36S. 
     
     
         6 . The kit of  claim 1 , wherein the amino acid is leucine, the non-radioactive atom is 13C, and the protein is amyloid-beta. 
     
     
         7 . The kit of  claim 1 , wherein the labeled amino acid is administered to the subject intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or orally. 
     
     
         8 . The kit of  claim 1 , wherein the biological sample is cerebral spinal fluid. 
     
     
         9 . The kit of  claim 1 , wherein the ratio of labeled protein to unlabeled protein is determined from the amounts of labeled and unlabeled protein detected by mass spectrometry. 
     
     
         10 . The kit of  claim 1 , wherein the metabolic index comprises the fractional synthesis rate (FSR) and the fractional clearance rate (FCR). 
     
     
         11 . The kit of  claim 1 , wherein the mammal is a human.