Metabolic defects associated with Down syndrome (trisomy 21, DS) and Alzheimer~s disease (AD) are examined, using bioanalytical techniques to probe brain chemistry. Using GC/MS, we reported a 50% increase in the myo-inositol (MI) concentration in cerebrospinal fluid (CSF) in DS adults. Accumulation of MI also was found in postmortem brain from DS subjects in the brain of the fetal trisomy 16 mouse (an animal model of DS). Using a stable isotope/mass spectrometric technique, higher MI uptake was found by cultured cortical neurons from the trisomy 16 mouse fetuses compared with diploid neurons, consistent with the overexpression of MI transporter gene found on mouse chromosome 16 and human chromosome 21. As MI plays a central role in signal transduction involving phospholipase C, the defect may be related to mental retardation in DS. Analytical methods were developed to analyze concentrations of physostigmine (anticholinesterase) and arecoline (cholinergic agonist) in plasma of human subjects given these drugs in clinical protocols involving positron-emission tomography and cognitive activation. Intravenous infusion schedules were designed on the basis of pharmacokinetic determinations. Additionally, two polyunsaturated molecular species of phosphatidylcholine exhibiting rapid radiolabeled arachidonate incorporation were identified in rat brain, with turnover rates of the order of minutes. These species likely play a important role in signal transduction (Ann Rep Z01 AG 00134 00134-13 LN).
