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Chapter 39 - Proton MR spectroscopy in aging and dementia

from Section 6 - Psychiatric and neurodegenerative diseases

Published online by Cambridge University Press:  05 March 2013

Jonathan H. Gillard
University of Cambridge
Adam D. Waldman
Imperial College London
Peter B. Barker
The Johns Hopkins University School of Medicine
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Neuroimaging techniques may have an important role in the clinical evaluation of dementia for early diagnosis, differential diagnosis, and monitoring of disease activity. The goal of this chapter is to review proton MR spectroscopy (MRS) literature in aging and dementia in order to demonstrate the potential clinical applications of the technique.

Normal aging

Age related changes in proton MRS measurements of the metabolites N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI) were investigated by several groups, and the results have been conflicting. There are reports showing that metabolite measurements are stable throughout aging;[1] one study showed a decrease in NAA, Cho, and Cr in gray matter,[2] and others an increase in Cho and Cr in the gray matter and white matter with aging.[3–7] As a whole, most studies agree that Cho and Cr increase with aging, and a majority of the studies agree that NAA levels are stable throughout aging (Table 39.1).

Clinical MR Neuroimaging
Physiological and Functional Techniques
, pp. 618 - 629
Publisher: Cambridge University Press
Print publication year: 2009

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Saunders, DE, Howe, FA, van den Boogaart, A, Griffiths, JR, Brown, MM. Aging of the adult human brain: in vivo quantitation of metabolite content with proton magnetic resonance spectroscopy. J Magn Reson Imaging 1999; 9: 711–716.3.0.CO;2-3>CrossRefGoogle ScholarPubMed
Charles, HC, Lazeyras, F, Krishnan, KR, et al. Proton spectroscopy of human brain: effects of age and sex. Prog Neuropsychopharmacol Biol Psychiatry 1994; 18: 995–1004.CrossRefGoogle ScholarPubMed
Chang, L, Ernst, T, Poland, RE, Jenden, DJ. In vivo proton magnetic resonance spectroscopy of the normal aging human brain. Life Sci 1996; 58: 2049–2056.CrossRefGoogle ScholarPubMed
Leary, SM, Brex, PA, MacManus, DG, et al. A (1)H magnetic resonance spectroscopy study of aging in parietal white matter: implications for trials in multiple sclerosis. Magn Reson Imaging 2000; 18: 455–459.CrossRefGoogle ScholarPubMed
Pfefferbaum, A, Adalsteinsson, E, Spielman, D, Sullivan, EV, Lim, KO. In vivo spectroscopic quantification of the N-acetyl moiety, creatine, and choline from large volumes of brain gray and white matter: effects of normal aging. Magn Reson Med 1999; 41: 276–284.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Schuff, N, Ezekiel, F, Gamst, AC, et al. Region and tissue differences of metabolites in normally aged brain using multislice 1H magnetic resonance spectroscopic imaging. Magn Reson Med 2001; 45: 899–907.CrossRefGoogle ScholarPubMed
Charlton, RA, McIntyre, DJ, Howe, FA, Morris, RG, Markus, HS. The relationship between white matter brain metabolites and cognition in normal aging: the GENIE study. Brain Res 2007; 1164: 108–116.CrossRefGoogle ScholarPubMed
Bates, TE, Strangward, M, Keelan, J, et al. Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo. Neuroreport 1996; 7: 1397–1400.CrossRefGoogle ScholarPubMed
Benarroch, EE. N-Acetylaspartate and N-acetylaspartylglutamate: neurobiology and clinical significance. Neurology 2008; 70: 1353–1357.CrossRefGoogle ScholarPubMed
Brooks, WM, Stidley, CA, Petropoulos, H, et al. Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma 2000; 17: 629–640.CrossRefGoogle ScholarPubMed
Bendszus, M, Reents, W, Franke, D, et al. Brain damage after coronary artery bypass grafting. Arch Neurol 2002; 59: 1090–1095.CrossRefGoogle ScholarPubMed
Hugg, JW, Kuzniecky, RI, Gilliam, FG, et al. Normalization of contralateral metabolic function following temporal lobectomy demonstrated by 1H magnetic resonance spectroscopic imaging. Ann Neurol 1996; 40: 236–239.CrossRefGoogle ScholarPubMed
Krishnan, KR, Charles, HC, Doraiswamy, PM, et al. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease. Am J Psychiatry 2003; 160: 2003–2011.CrossRefGoogle ScholarPubMed
Modrego, PJ. Predictors of conversion to dementia of probable Alzheimer type in patients with mild cognitive impairment. Curr Alzheimer Res 2006; 3: 161–170.CrossRefGoogle ScholarPubMed
Long, JM, Mouton, PR, Jucker, M, Ingram, DK. What counts in brain aging? Design-based stereological analysis of cell number. J Gerontol A Biol Sci Med Sci 1999; 54: B407–B417.CrossRefGoogle ScholarPubMed
Valenzuela, MJ, Sachdev, PS, Wen, W, et al. Dual voxel proton magnetic resonance spectroscopy in the healthy elderly: subcortical–frontal axonal N-acetylaspartate levels are correlated with fluid cognitive abilities independent of structural brain changes. Neuroimage 2000; 12: 747–756.CrossRefGoogle ScholarPubMed
Zimmerman, ME, Pan, JW, Hetherington, HP, et al. Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults. Neurology 2008; 70: 1594–1600.CrossRefGoogle ScholarPubMed
Americal Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised. Washington, DC: American Psychiatric Press, 1987.Google Scholar
Holmes, C, Cairns, N, Lantos, P, Mann, A. Validity of current clinical criteria for Alzheimer’s disease, vascular dementia and dementia with Lewy bodies. Br J Psychiatry 1999; 174: 45–50.CrossRefGoogle ScholarPubMed
Schneider, JA, Arvanitakis, Z, Bang, W, Bennett, DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007; 69: 2197–2204.CrossRefGoogle ScholarPubMed
Massoud, F, Devi, G, Stern, Y, et al. A clinicopathological comparison of community-based and clinic-based cohorts of patients with dementia. Arch Neurol 1999; 56: 1368–1373.CrossRefGoogle ScholarPubMed
Huang, W, Alexander, GE, Chang, L, et al. Brain metabolite concentration and dementia severity in Alzheimer’s disease: a (1)H MRS study. Neurology 2001; 57: 626–632.CrossRefGoogle ScholarPubMed
Jessen, F, Block, W, Traber, F, et al. Proton MR spectroscopy detects a relative decrease of N-acetylaspartate in the medial temporal lobe of patients with AD. Neurology 2000; 55: 684–688.CrossRefGoogle ScholarPubMed
Klunk, WE, Panchalingam, K, McClure, RJ, Stanley, JA, Pettegrew, JW. Metabolic alterations in postmortem Alzheimer’s disease brain are exaggerated by Apo-E4. Neurobiol Aging 1998; 19: 511–515.CrossRefGoogle ScholarPubMed
Meyerhoff, DJ, MacKay, S, Constans, JM, et al. Axonal injury and membrane alterations in Alzheimer’s disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol 1994; 36: 40–47.CrossRefGoogle ScholarPubMed
Miller, BL, Moats, RA, Shonk, T, et al. Alzheimer disease: depiction of increased cerebral myo-inositol with proton MR spectroscopy. Radiology 1993; 187: 433–437.CrossRefGoogle ScholarPubMed
Mohanakrishnan, P, Fowler, AH, Vonsattel, JP, et al. Regional metabolic alterations in Alzheimer’s disease: an in vitro 1H NMR study of the hippocampus and cerebellum. J Gerontol Biol Sci Med Sci 1997; 52: B111–B117.CrossRefGoogle Scholar
Rose, SE, de Zubicaray, GI, Wang, D, et al. A 1H MRS study of probable Alzheimer’s disease and normal aging: implications for longitudinal monitoring of dementia progression. Magn Reson Imaging 1999; 17: 291–299.CrossRefGoogle ScholarPubMed
Schuff, N, Capizzano, AA, Du, AT, et al. Selective reduction of N-acetylaspartate in medial temporal and parietal lobes in AD. Neurology 2002; 58: 928–935.CrossRefGoogle ScholarPubMed
Moats, RA, Watson, L, Shonk, T, et al. Added value of automated clinical proton MR spectroscopy of the brain. J Comput Assist Tomogr 1995; 19: 480–491.CrossRefGoogle Scholar
Kantarci, K, Petersen, RC, Boeve, BF, et al. 1H MR spectroscopy in common dementias. Neurology 2004; 63: 1393–1398.CrossRefGoogle ScholarPubMed
Moats, RA, Ernst, T, Shonk, TK, Ross, BD. Abnormal cerebral metabolite concentrations in patients with probable Alzheimer disease. Magn Reson Med 1994; 32: 110–115.CrossRefGoogle ScholarPubMed
Parnetti, L, Tarducci, R, Presciutti, O, et al. Proton magnetic resonance spectroscopy can differentiate Alzheimer’s disease from normal aging. Mech Ageing Devel 1997; 97: 9–14.CrossRefGoogle ScholarPubMed
Schuff, N, Amend, D, Ezekiel, F, et al. Changes of hippocampal N-acetyl aspartate and volume in Alzheimer’s disease. A proton MR spectroscopic imaging and MRI study. Neurology 1997; 49: 1513–1521.CrossRefGoogle ScholarPubMed
Petrovitch, H, White, LR, Ross, GW, et al. Accuracy of clinical criteria for AD in the Honolulu–Asia Aging Study, a population-based study. Neurology 2001; 57: 226–234.CrossRefGoogle ScholarPubMed
Ernst, T, Chang, L, Melchor, R, Mehringer, CM. Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe H–1 MR spectroscopy. Radiology 1997; 203: 829–836.CrossRefGoogle ScholarPubMed
Zhu, X, Schuff, N, Kornak, J, et al. Effects of Alzheimer disease on fronto-parietal brain N-acetyl aspartate and myo-inositol using magnetic resonance spectroscopic imaging. Alzheimer Dis Assoc Disord 2006; 20: 77–85.CrossRefGoogle ScholarPubMed
Braak, H, Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.CrossRefGoogle ScholarPubMed
Kantarci, K, Jack, CR, Xu, YC, et al. Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease: A 1H MRS study. Neurology 2000; 55: 210–217.CrossRefGoogle ScholarPubMed
Adalsteinsson, E, Sullivan, EV, Kleinhans, N, Spielman, DM, Pfefferbaum, A. Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer’s disease. Lancet 2000; 355: 1696–1697.CrossRefGoogle ScholarPubMed
MacKay, S, Ezekiel, F, Di Sclafani, V, et al. Alzheimer disease and subcortical ischemic vascular dementia: evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging. Radiology 1996; 198: 537–545.CrossRefGoogle ScholarPubMed
Wurtman, RJ BJ, Marie, JC. Autocannibalism of choline-containing membrane phospholipids in the pathogenesis of Alzheimer’s disease. Neurochem Int 1985(7): 369–372.CrossRefGoogle ScholarPubMed
Bartha, R, Smith, M, Rupsingh, R, et al. High field (1)H MRS of the hippocampus after donepezil treatment in Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 786–793.CrossRefGoogle ScholarPubMed
Satlin, A, Bodick, N, Offen, WW, Renshaw, PF. Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist. Am J Psychiatry 1997; 154: 1459–1461.Google ScholarPubMed
Frederick, BB, Satlin, A, Yurgelun-Todd, DA, Renshaw, PF. In vivo proton magnetic resonance spectroscopy of Alzheimer’s disease in the parietal and temporal lobes. Biol Psychiatry 1997; 42: 147–150.CrossRefGoogle ScholarPubMed
Glanville, NT, Byers, DM, Cook, HW, Spence, MW, Palmer, FB. Differences in the metabolism of inositol and phosphoinositides by cultured cells of neuronal and glial origin. Biochim Biophys Acta 1989; 1004: 169–179.CrossRefGoogle Scholar
Bitsch, A, Bruhn, H, Vougioukas, V, et al. Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol 1999; 20: 1619–1627.Google ScholarPubMed
Ross, BD, Bluml, S, Cowan, R, et al. In vivo MR spectroscopy of human dementia. Neuroimaging Clin N Am 1998; 8: 809–822.Google ScholarPubMed
Soher, BJ, Vermathen, P, Schuff, N, et al. Short TE in vivo (1)H MR spectroscopic imaging at 1.5 T: acquisition and automated spectral analysis. Magn Reson Imaging 2000; 18: 1159–1165.CrossRefGoogle Scholar
Doraiswamy, PM, Charles, HC, Krishnan, KR. Prediction of cognitive decline in early Alzheimer’s disease. Lancet 1998; 352: 1678.CrossRefGoogle ScholarPubMed
Kantarci, K, Xu, Y, Shiung, MM, et al. Comparative diagnostic utility of different MR modalities in mild cognitive impairment and Alzheimer’s disease. Dement Geriatr Cogn Discord 2002; 14: 198–207.CrossRefGoogle ScholarPubMed
Kwo-On-Yuen, PF, Newmark, RD, Budinger, TF, et al. Brain N-acetyl-l-aspartic acid in Alzheimer’s disease: a proton magnetic resonance spectroscopy study. Brain Res 1994; 667: 167–174.CrossRefGoogle ScholarPubMed
Schuff, N, Amend, DL, Meyerhoff, DJ, et al. Alzheimer disease: quantitative H-1 MR spectroscopic imaging of frontoparietal brain. Radiology 1998; 207: 91–102.CrossRefGoogle ScholarPubMed
Kantarci, K, Smith, GE, Ivnik, RJ, et al. 1H magnetic resonance spectroscopy, cognitive function, and apolipoprotein E genotype in normal aging, mild cognitive impairment and Alzheimer’s disease. J Int Neuropsychol Soc 2002; 8: 934–942.CrossRefGoogle ScholarPubMed
Chantal, S, Braun, CM, Bouchard, RW, Labelle, M, Boulanger, Y. Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease. Brain Res 2004; 1003: 26–35.CrossRefGoogle ScholarPubMed
Schenk, D, Barbour, R, Dunn, W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173–177.CrossRefGoogle ScholarPubMed
Kordower, JH, Chu, Y, Stebbins, GT, et al. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 2001; 49: 202–213.3.0.CO;2-3>CrossRefGoogle ScholarPubMed
Jack, CR, Jr., Shiung, MM, Gunter, JL, et al. Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology 2004; 62: 591–600.CrossRefGoogle ScholarPubMed
Catani, M, Cherubini, A, Howard, R, et al. (1)H-MR spectroscopy differentiates mild cognitive impairment from normal brain aging. Neuroreport 2001; 12: 2315–2317.CrossRefGoogle ScholarPubMed
Huang, W, Alexander, GE, Daly, EM, et al. High brain myo-inositol levels in the predementia phase of Alzheimer’s disease in adults with Down’s syndrome: a 1H MRS study. Am J Psychiatry 1999; 156: 1879–1886.Google ScholarPubMed
Ackl, N, Ising, M, Schreiber, YA, et al. Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 2005; 384: 23–28.CrossRefGoogle ScholarPubMed
Franczak, M, Prost, RW, Antuono, PG, et al. Proton magnetic resonance spectroscopy of the hippocampus in patients with mild cognitive impairment: a pilot study. J Comput Assist Tomogr 2007; 31: 666–670.CrossRefGoogle ScholarPubMed
Chao, LL, Schuff, N, Kramer, JH, et al. Reduced medial temporal lobe N-acetylaspartate in cognitively impaired but nondemented patients. Neurology 2005; 64: 282–289.CrossRefGoogle ScholarPubMed
Metastasio, A, Rinaldi, P, Tarducci, R, et al. Conversion of MCI to dementia: role of proton magnetic resonance spectroscopy. Neurobiol Aging 2006; 27: 926–932.CrossRefGoogle ScholarPubMed
Fernandez, A, Garcia-Segura, JM, Ortiz, T, et al. Proton magnetic resonance spectroscopy and magnetoencephalographic estimation of delta dipole density: a combination of techniques that may contribute to the diagnosis of Alzheimer’s disease. Dement Geriatr Cogn Disord 2005; 20: 169–177.CrossRefGoogle Scholar
den Heijer, T, Sijens, PE, Prins, ND, et al. MR spectroscopy of brain white matter in the prediction of dementia. Neurology 2006; 66: 540–544.CrossRefGoogle Scholar
Godbolt, AK, Waldman, AD, MacManus, DG, et al. MRS shows abnormalities before symptoms in familial Alzheimer disease. Neurology 2006; 66: 718–722.CrossRefGoogle ScholarPubMed
Jessen, F, Block, W, Traber, F, et al. Decrease of N-acetylaspartate in the MTL correlates with cognitive decline of AD patients. Neurology 2001; 57: 930–932.CrossRefGoogle ScholarPubMed
Kantarci, K, Weigand, SD, Petersen, RC, et al. Longitudinal (1)H MRS changes in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 2007; 28: 1330–1339.CrossRefGoogle ScholarPubMed
Marjanska, M, Curran, GL, Wengenack, TM, et al. Monitoring disease progression in transgenic mouse models of Alzheimer’s disease with proton magnetic resonance spectroscopy. Proc Natl Acad Sci USA 2005; 102: 11906–11910.CrossRefGoogle ScholarPubMed
Jessen, F, Traeber, F, Freymann, K, et al. Treatment monitoring and response prediction with proton MR spectroscopy in AD. Neurology 2006; 67: 528–530.CrossRefGoogle ScholarPubMed
Kantarci, K, Knopman, DS, Dickson, DW, et al. Alzheimer disease: postmortem neuropathologic correlates of antemortem 1H MR spectroscopy metabolite measurements. Radiology 2008; 248: 210–220.CrossRefGoogle ScholarPubMed
Kattapong, VJ, Brooks, WM, Wesley, MH, Kodituwakku, PW, Rosenberg, GA. Proton magnetic resonance spectroscopy of vascular- and Alzheimer-type dementia. Arch Neurol 1996; 53: 678–680.CrossRefGoogle ScholarPubMed
Bennett, DA, Schneider, JA, Bienias, JL, Evans, DA, Wilson, RS. Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology 2005; 64: 834–841.CrossRefGoogle ScholarPubMed
Waldman, AD, Rai, GS, McConnell, JR, Chaudry, M, Grant, D. Clinical brain proton magnetic resonance spectroscopy for management of Alzheimer’s and sub-cortical ischemic vascular dementia in older people. Arch Gerontol Geriatr 2002; 35: 137–142.CrossRefGoogle ScholarPubMed
McKeith, IG, Dickson, DW, Lowe, J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65: 1863–1872.CrossRefGoogle ScholarPubMed
Hamilton, RL. Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 2000; 10: 378–384.CrossRefGoogle ScholarPubMed
Gomez-Isla, T, Growdon, WB, McNamara, M, et al. Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies. Neurology 1999; 53: 2003–2009.CrossRefGoogle ScholarPubMed
Molina, JA, Garcia-Segura, JM, Benito-Leon, J, et al. Proton magnetic resonance spectroscopy in dementia with Lewy bodies. Eur Neurol 2002; 48: 158–163.CrossRefGoogle ScholarPubMed
Tiraboschi, P, Hansen, LA, Alford, M, et al. Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry 2002; 59: 946–951.CrossRefGoogle ScholarPubMed
McKeith, IG, Ballard, CG, Perry, RH, et al. Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology 2000; 54: 1050–1058.CrossRefGoogle Scholar
Garrard, P, Schott, JM, MacManus, DG, et al. Posterior cingulate neurometabolite profiles and clinical phenotype in frontotemporal dementia. Cogn Behav Neurol 2006; 19: 185–189.CrossRefGoogle ScholarPubMed
Mihara, M, Hattori, N, Abe, K, Sakoda, S, Sawada, T. Magnetic resonance spectroscopic study of Alzheimer’s disease and frontotemporal dementia/Pick complex. Neuroreport 2006; 17: 413–416.CrossRefGoogle ScholarPubMed
Kantarci, K, Reynolds, G, Petersen, RC, et al. Proton MR spectroscopy in mild cognitive impairment and Alzheimer disease: comparison of 1.5 and 3 T. AJNR Am J Neuroradiol 2003; 24: 843–849.Google ScholarPubMed

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