Arch Gen Psychiatry 63(12): 1360-1365 (2005 Dec)

Hippocampal Myo-inositol and Cognitive Ability in Adults With Down Syndrome: An In Vivo Proton Magnetic Resonance Spectroscopy Study

Felix Beacher; Andy Simmons; Eileen Daly; Verinder Prasher; Claire Adams; Maria Luisa Margallo-Lana; Robin Morris; Simon Lovestone; Kieran Murphy; Declan GM Murphy
Genetik Arastirma Merkezi, Cerrahpasa Tip Fakultesi, Istanbul Universitesi, Cerrahpasa, Section of Brain Maturation, Department of Psychological Medicine, Neuroimaging Research Group, and Departments of Psychology and Old Age Psychiatry and Neuroscience, Institute of Psychiatry, London, England; Institute for Ageing and Health, Wolfson Research Unit, Newcastle General Hospital, Newcastle upon Tyne, England; Greenfields Monyhull Hospital, Kings Norton, Birmingham, England; College of Surgeons, Dublin, Ireland.
CONTEXT: Down syndrome (DS) is the most common genetic cause of mental retardation. However, the biological determinants of this are poorly understood. The serum sodium/myo-inositol cotransporter gene is located on chromosome 21, and myo-inositol affects neuronal survival and function. Nevertheless, few in vivo studies have examined the role of myo-inositol in DS. OBJECTIVE: To determine if people with DS have significant differences in brain myo-inositol concentration from controls and if, within people with DS, this is related to cognitive ability. DESIGN: A case-control study. SETTING: Outpatient. PARTICIPANTS: The sample was composed of 38 adults with DS without dementia (age range, 18-66 years) and 42 healthy controls (age range, 19-66 years). The DS and control groups did not differ significantly in age, sex, ethnic origin, apolipoprotein E status, or handedness. MAIN OUTCOME MEASURES: Hippocampal myo-inositol concentration and cognitive performance, as measured by the Cambridge Cognitive Examination. RESULTS: Hippocampal myo-inositol concentration was significantly higher in people with DS than in controls (P = .006), and within people with DS, increased myo-inositol concentration was significantly negatively correlated with overall cognitive ability (P = .04). CONCLUSIONS: Adults with DS have a significantly increased brain concentration of myo-inositol, and this is associated with reduced cognitive ability. Future studies are required to relate myo-inositol concentration in people with DS to brain development and increased risk for developing Alzheimer disease.
International Society for Magnetic Resonance in Medicine Seventh Scientific Meeting, Philadelphia, PA (1999 May 24-8)

Brain Myo-Inositol in Children with Down Syndrome — an In Vivo Proton MRS study

*S.F. Dreha, G.T. Berry, Z.J. Wang, R.A. Zimmerman
The Children's Hospital of Philadelphia and *University of Pennsylvania Philadelphia, PA, USA
Discussion. With in vivo ¹H-MRS, we demonstrated a 28% increase of m1 levels in basal ganglia in children with DS compared to an age matched control group. The plasma osmolality of all DS patient was within normal range. We hypothesize, that the increase of m1 could be related to the presence of the extra copy of the SLC5A3 gene in the trisomic 21 cells. Studies on trisomy 16 mice, the animal model for DS reported elevated m1 levels in brain, which support the hypothesis. The extra gene copy should result in a 50% increase in brain m1 in DS patients, as has been demonstrated for m1 levels in CSF in a group of adults with DS. An explanation for the discrepancy is not yet available. The 28% increase in brain m1 could be pathophysiologically significant, if the increased influx of m1 and Na+ leads to a perturbation in cell volume and sodium content or secondarily affects the levels of other relevant ions. Further studies on brain m1 metabolism in DS patients are warranted.
J Pediatr 135(1): 94-7 (1999 Jul)

In vivo brain myo-inositol levels in children with Down syndrome

Berry GT, Wang ZJ, Dreha SF, Finucane BM, Zimmerman RA
Department of Pediatrics, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
The Na+/myo-inositol cotransporter (SLC5A3) gene, located on the long arm of human chromosome 21, may play a key role in osmoregulation including the regulation of levels of the "idiogenic osmole," myo-inositol, in brain cells. To determine whether the levels of myo-inositol are increased in the basal ganglia of children with Down syndrome, we performed in vivo brain hydrogen 1-nuclear magnetic resonance or 1H-magnetic resonance spectroscopy and measured plasma osmolality in a cohort of children with trisomy 21. Myo-inositol is elevated in the corpus striatum of infants and children with Down syndrome, even in the absence of hypertonic stress.
Am J Psychiatry 156(12): 1879-86 (1999 Dec)

High Brain myo-Inositol Levels in the Predementia Phase of Alzheimer's Disease in Adults With Down's Syndrome: A ¹H MRS Study

Wei Huang, Ph.D., Gene E. Alexander, Ph.D., Eileen M. Daly, B.S., H. Umesha Shetty, Ph.D., Jack S. Krasuski, M.D., Stanley I. Rapoport, M.D., and Mark B. Schapiro, M.D.
Laboratory of Neurosciences, National Institute on Aging, Clinical Center, NIH, Bethesda, MD, USA
OBJECTIVE: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myoinositol and N-acetyl-aspartate. The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome. METHOD: The authors used 1H magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects. RESULTS: Concentrations of myoinositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group. CONCLUSIONS: The approximately 50% higher level of myo-inositol in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myoinositol levels in symptomatic Alzheimer's disease.
J Clin Invest 95(2): 542-6 (1995 Feb)

Polyol profiles in Down syndrome. myo-Inositol, specifically, is elevated in the cerebrospinal fluid

H. Umesha Shetty, Mark B. Schapiro, Harold W. Holloway, and Stanley I. Rapoport
Laboratory of Neurosciences, National Institute of Aging, National Institutes of Health, Bethesda, Maryland 20892
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.