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Polyol Profiles in Down Syndrome. Myo-Inositol, Specifically, Is Elevated in the Cerebrospinal Fluid

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Polyol Profiles in Down Syndrome. Myo-Inositol, Specifically, Is Elevated in the Cerebrospinal Fluid Polyol profiles in Down syndrome. myo-Inositol, specifically, is elevated in the cerebrospinal fluid. H U Shetty, … , H W Holloway, S I Rapoport J Clin Invest. 1995;95(2):542-546. https://doi.org/10.1172/JCI117696. Research Article Polyols are reduction products of aldoses and ketoses; their concentrations in tissues can reflect carbohydrate metabolism. Several polyol species were quantitated in cerebrospinal fluid (CSF) and plasma from 10 Down Syndrome (trisomy 21) subjects between the ages of 22 and 63 years (3 of whom were demented) and from 10 healthy age- matched controls, using a gas chromatographic/mass spectrometric technique. The mean CSF concentration and the mean CSF/plasma concentration ratio of myo-inositol were significantly elevated in Down syndrome compared with controls, but were not correlated with the presence of dementia in the Down subjects. Plasma myo-inositol was not significantly altered in these subjects. No significant difference between Down syndrome and controls was found for CSF concentrations of mannitol, sorbitol, galactitol, ribitol, arabitol, or 1,5-anhydrosorbitol, but plasma mannitol, ribitol and arabitol were elevated in Down syndrome. The present observation provides new impetus for studying synthesis and transport of myo-inositol as well as phosphatidylinositol cycle in trisomy 21 disorder. Find the latest version: https://jci.me/117696/pdf Polyol Profiles in Down Syndrome myo-lnositol, Specifically, Is Elevated in the Cerebrospinal Fluid H. Umesha Shetty, Mark B. Schapiro, Harold W. Holloway, and Stanley 1. Rapoport Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892 Abstract catabolism, and regulatory pathways) directly or by affecting gene expression of other chromosomes and subsequent molecu- Polyols are reduction products of aldoses and ketoses; their lar events. We thus sought to identify metabolites whose altered concentrations in tissues can reflect carbohydrate metabo- levels in brain might contribute to pathophysiology relevant lism. Several polyol species were quantitated in cerebrospi- to DS. Polyols, the ubiquitous metabolites of sugars, play a nal fluid (CSF) and plasma from 10 Down Syndrome (tri- significant role in diabetic neuropathy (3), uremic polyneuropa- somy 21) subjects between the ages of 22 and 63 years (3 thy (4), and galactosemia (5). In these metabolic disorders, of whom were demented) and from 10 healthy age-matched decreased Na+/K+ -ATPase, altered electrical properties and controls, using a gas chromatographic/mass spectrometric other plasma membrane abnormalities are associated with ele- technique. The mean CSF concentration and the mean CSF/ vated tissue polyols. Additionally, cataract formation is a major plasma concentration ratio of myo-inositol were significantly pathological consequence of abnormal metabolism of polyols elevated in Down syndrome compared with controls, but (6). These pathophysiologic abnormalities reminiscent of cer- were not correlated with the presence of dementia in the tain DS phenotypes guided us in an examination of polyols in Down subjects. Plasma myo-inositol was not significantly DS subjects. altered in these subjects. No significant difference between Here we report the results of quantitative profiling of polyols Down syndrome and controls was found for CSF concentra- in cerebrospinal fluid (CSF) and plasma from DS adults and tions of mannitol, sorbitol, galactitol, ribitol, arabitol, or 1,5- age-matched healthy controls. As polyols are reduction products anhydrosorbitol, but plasma mannitol, ribitol and arabitol of sugars, analysis of polyol levels in DS may be used to probe were elevated in Down syndrome. The present observation glycolytic, pentose phosphate and the connected pathways for provides new impetus for studying synthesis and transport abnormalities related to this genetic disorder. of myo-inositol as well as phosphatidylinositol cycle in tri- somy 21 disorder. (J. Clin. Invest. 1995. 95:542-546.) Key Methods words: carbohydrates - phosphatidylinositols * brain * tri- somy * Alzheimer disease Selection of subjects. All DS subjects had trisomy 21 except for one demented older subject who had a mosaic translocation, mos46,xx/ Introduction 46,xx,-21,+(21q;21q) (7). DS subjects and healthy volunteers were carefully screened according to procedures previously described (8). The Down syndrome (DS)' (trisomy 21) phenotype is charac- The subjects underwent a review of medical history and a physical and terized by a multitude of morphological and functional abnor- neurological examination (blood and urine tests, electrocardiograph, malities, including short stature, microcephaly, cardiovascular chest radiograph, electroencephalograph, and structural brain imaging). malformations, immunological disorders, leukemia, and cata- One young DS subject had a mild depression. The control subjects had racts. In addition, mental retardation and, after the fourth decade no history of neurological disorder; these subjects and the selected DS of life, neuropathological and neurochemical changes similar subjects were free of medical conditions (such as hypertension, seizures, diabetes, malignancy, and to those observed in Alzheimer disease are the universal maii- trauma) that might have affected the central nervous festations of this genetic anomaly (1, 2). At the cellular system. Except for thyroid replacement in several DS subjects, level, no DS or control subject was taking medication. No subject had a history altered electrical decreased + + properties, Na /K -ATPase activ- of alcohol or drug abuse. The DS group consisted of 10 adults, 5 males, ity and exaggerated response to certain drugs point to dysfunc- and 5 females, with ages ranging from 22 to 63 (43.3± 15.1, mean±SD) tion of the plasma membrane in DS. years. Four of these were classified as young DS subjects with ages In DS, gene products of the extra chromosome 21 may cause ranging from 22 to 34 (27.2±4.9, mean±SD) years. Ages of remaining abnormal levels of certain metabolites (by synthesis, transport, six older DS subjects ranged from 45 to 64 (54.0±7.3, mean±SD) years. Three of the older DS subjects were found by examination, history, and cognitive testing to be demented (9, 10). Subsequently, 2 of the other 3 older DS subjects became demented. The control group consisted of Address correspondence to H. Umesha Shetty, Ph.D., Laboratory of 10 subjects, 7 males, and 3 females, with ages ranging from 23 to 69 Neurosciences, National Institute on Aging, National Institutes of (47.5±17.1, mean±SD) years. No control subject was demented. The Health, Building 10, Room 6C 103, Bethesda, MD 20892. Phone: 301- research was conducted under National Institutes of Health protocols 496-8970; FAX: 301-402-0074. 81AG1O (for subjects with DS) and 80AG26 (for controls). Received for publication 6 July 1994 and in revisedform 7 October Sample collection. All subjects were free of medication for at least 1994. 2 wk before lumbar puncture and were placed on a diet that was low in monoaminergic precursors for 72 h (11). The morning after overnight 1. Abbreviations used in this paper: CSF, cerebrospinal fluid; DS, Down bed rest and fasting, lumbar punctures were performed with subjects in syndrome; RcsF, cerebrospinal fluid to plasma concentration ratio. the lateral decubitus position. After a sterile preparation, the L3-4 interspace was infiltrated with 1% lidocaine. A 20-gauge spinal needle The Journal of Clinical Investigation, Inc. then was inserted into the spinal subarachnoid space. Specimens were Volume 95, February 1995, 542-546 analyzed only if the CSF was clear, with normal cell counts, protein, 542 Shetty et al. and glucose. The first 12 ml of CSF were pooled and immediately (not shown) the peak for xylitol was distinct, allowing reliable placed on wet ice. One-ml aliquots then were frozen at -80'C until quantitation of the polyol. There was no gross difference be- assayed. Just before the lumbar puncture, venous blood was withdrawn tween the ion chromatograms of control and DS subjects. Only through an indwelling intravenous catheter placed 10 h before (to mini- the peak area ratio of polyol to internal standard was altered mize acute changes of blood and CSF neurotransmitters). Stable blood pressures and heart rates were recorded over three or more successive for certain polyols in DS. 10-min periods before venous sampling. These measurements were CSF polyol concentrations for healthy control and DS sub- made in order to assess the level of stress, which could in turn influence jects are shown in Table I. Mean concentrations of ribitol, arabi- the concentrations of some neurotransmitters. The blood was placed in tol, 1,5-anhydrosorbitol, mannitol, sorbitol and galactitol in DS heparinized polypropylene tubes and immediately centrifuged at 5,000 were not significantly different from those of control subjects. g at 40C for 20 min. One-ml aliquots of the resultant plasma were As with control subjects, the CSF concentration of xylitol was removed and then stored at -80'C until assayed. negligibly low in DS. The CSF level of myo-inositol, Gas chromatographic/mass spectrometric assay of polyols. Polyol 36.32+8.02 ng/gl (mean±SD), in DS was significantly (P species in CSF and plasma were quantitated by a method developed in < 0.005) higher (by 49%) than 24.35+4.20 ng/Ml found in our laboratory (Shetty, H. U., H. W. Holloway, and S. I. Rapoport, control subjects. In each group of 10 subjects, the CSF myo- manuscript submitted
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