Reduced N-acetylaspartate is consistent with axonal dysfunction in cerebral small vessel disease
Corresponding Author
Arani Nitkunan
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Centre for Clinical Neuroscience, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.Search for more papers by this authorRebecca A. Charlton
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Search for more papers by this authorThomas R. Barrick
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Search for more papers by this authorDominick J. O. McIntyre
Department of Basic Medical Sciences, St George's, University of London, London, UK
Search for more papers by this authorFranklyn A. Howe
Department of Basic Medical Sciences, St George's, University of London, London, UK
Search for more papers by this authorHugh S. Markus
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Search for more papers by this authorCorresponding Author
Arani Nitkunan
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Centre for Clinical Neuroscience, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.Search for more papers by this authorRebecca A. Charlton
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Search for more papers by this authorThomas R. Barrick
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Search for more papers by this authorDominick J. O. McIntyre
Department of Basic Medical Sciences, St George's, University of London, London, UK
Search for more papers by this authorFranklyn A. Howe
Department of Basic Medical Sciences, St George's, University of London, London, UK
Search for more papers by this authorHugh S. Markus
Centre for Clinical Neuroscience, St George's, University of London, London, UK
Search for more papers by this authorAbstract
Background:
Cerebral small vessel disease (SVD) is an important cause of cognitive impairment, but the pathophysiological mechanisms remain unclear. We used 1H MRS to investigate brain metabolic differences between patients with SVD and controls and correlated this with cognition.
Methods:
35 patients with SVD (lacunar stroke and radiological evidence of confluent leukoaraiosis) and 35 controls underwent multi-voxel spectroscopic imaging of white matter to obtain absolute metabolite concentrations of N-acetylaspartate (NAA), total creatines, total cholines, myo-inositol, and lactate. A range of cognitive tests was performed on patients with SVD, and composite scores were calculated.
Results:
Scans of sufficient quality for data analysis were available in 29 cases and 35 controls. NAA was significantly reduced in patients compared with controls (lower by 7.27%, P = 0.004). However, when lesion load within each individual voxel (mean 22% in SVD vs 5% in controls, P < 0.001) was added as a covariate, these differences were no longer significant, suggesting that the metabolite differences arose primarily from differences in lesioned tissue. In patients with SVD, there was no correlation between cognitive scores and any brain metabolite. No lactate, an indicator of anaerobic metabolism, was detected.
Conclusions:
The most consistent change in SVD is a reduction in NAA, a marker of neuronal integrity. The lack of correlation with cognition does not support the use of MRS as a surrogate disease marker. Copyright © 2008 John Wiley & Sons, Ltd.
REFERENCES
- 1 Hachinski V, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987; 44: 21–23.
- 2 Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 2002; 1: 426–436.
- 3 Sabri O, Ringelstein E, Hellwig D, Schneider R, Schreckenberger M, Kaiser H, Mull M, Buell U. Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy. Stroke 1999; 30: 556–566.
- 4 Fukuda H, Kobayashi S, Okada K, Tsunematsu T. Frontal white matter lesions and dementia in lacunar infarction. Stroke 1990; 21: 1143–1149.
- 5 Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Radner H, Lechner H. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993; 43: 1683–1689.
- 6 Revesz T, Hawkins CP, du Boulay EP, Barnard RO, McDonald WI. Pathological findings correlated with magnetic resonance imaging in subcortical arteriosclerotic encephalopathy (Binswanger's disease). J Neurol Neurosurg Psychiatry 1989; 52: 1337–1344.
- 7 van Swieten J, van den Hout J, van Ketel B, Hijdra A, Wokke J, van Gijn J. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain 1991; 114: 761–774.
- 8 Filippi M, Rocca MA, Comi G. The use of quantitative magnetic- resonance-based techniques to monitor the evolution of multiple sclerosis. Lancet Neurol 2003; 2: 337–346.
- 9 Simmons ML, Frondoza CG, Coyle JT. Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 1991; 45: 37–45.
- 10 Oppenheimer SM, Bryan RN, Conturo TE, Soher BJ, Preziosi TJ, Barker PB. Proton magnetic resonance spectroscopy and gadolinium-DTPA perfusion imaging of asymptomatic MRI white matter lesions. Magn Reson Med 1995; 33: 61–68.
- 11 Auer D, Schirmer T, Heidenreich J, Herzog J, Putz B, Dichgans M. Altered white and gray matter metabolism in CADASIL: a proton MR spectroscopy and 1H-MRSI study. Neurology 2001; 56: 635–642.
- 12 Hund-Georgiadis M, Norris D, Guthke T, von Cramon D. Characterisation of cerebral small vessel disease by proton spectroscopy and morphological magnetic resonance. Cerebrovasc Dis 2001; 12: 82–90.
- 13 Brooks WM, Wesley MH, Kodituwakku PW, Garry PJ. Rosenberg GA: 1H-MRS differentiates white matter hyperintensities in subcortical arteriosclerotic encephalopathy from those in normal elderly. Stroke 1997; 28: 1940–1943.
- 14 Schmidt R, Scheltens P, Erkinjuntti T, Pantoni L, Markus HS, Wallin A, Barkhof F, Fazekas F, for the European Task Force on Age-Related White Matter Changes. White matter lesion progression: a surrogate endpoint for trials in cerebral small-vessel disease. Neurology 2004; 63: 139–144.
- 15 O'Sullivan M, Morris RG, Markus HS. Brief cognitive assessment for patients with cerebral small vessel disease. J Neurol Neurosurg Psychiatry 2005; 76: 1140–1145.
- 16 Adams H, Bendixen B, Kappelle L, Biller J, Love BB, Gordon DL, Marsh EE, III. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35–41.
- 17 Nelson H, Willison J. National Adult Reading Test Manual, 2nd ed. NFER-Nelson: Windsor, 1991.
- 18 Wechsler D. Wechsler Abbreviated Scale of Intelligence. The Psychological Corporation: New York, 1999.
- 19 Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.
- 20 Wechsler D, Wycherley R, Benjamin L. Wechsler Memory Scale - III. The Psychological Corporation: London, 1998.
- 21 Delis D, Kaplan E, Kramer JH. The Delis-Kaplan Executive Function System. The Psychological Corporation: San Antonio, 2001.
- 22 Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed 2001; 14: 260–264.
- 23 McLean MA, Woermann FG, Barker GJ, Duncan JS. Quantitative analysis of short echo time 1H-MRSI of cerebral gray and white matter. Magn Reson Med 2000; 44: 401–411.
- 24 McIntyre DJ, Charlton RA, Markus HS, Howe FA. Long and short echo time proton magnetic resonance spectroscopic imaging of the healthy aging brain. J. Magn Reson Imaging 2007; 26: 1596–1606.
- 25 Doyle T, Bedell B, Narayana P. Relative concentrations of proton MR visible neurochemicals in grey and white matter in human brain. Magn Reson Med 1995; 33: 755–759.
- 26 Ross B, Bluml S. Magnetic resonance spectroscopy of the human brain. Anat Rec 2001; 265: 54–84.
- 27 Narayana P, Doyle T, Lai D, Wolinsky J. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998; 43: 56–71.
- 28 Walker PM, Ben SD, Lalande A, Giroud M, Brunotte F. Time course of NAA T2 and ADC(w) in ischaemic stroke patients: 1H MRS imaging and diffusion-weighted MRI. J Neurol Sci 2004; 220: 23–28.
- 29 Kamada K, Houkin K, Hida K, Matsuzawa H, Iwasaki Y, Abe H, Nakada T. Localized proton spectroscopy of focal brain pathology in humans: significant effects of edema on spin-spin relaxation time. Magn Reson Med 1994; 31: 537–540.
- 30 Kamada K, Houkin K, Iwasaki Y, Abe H, Kashiwaba T. In vivo proton magnetic resonance spectroscopy for metabolic changes of human brain edema. Neurol Med Chir 1994; 34: 676–681.
- 31
Saunders DE,
Howe FA,
van den BA,
Griffiths JR,
Brown MM.
Aging of the adult human brain: in vivo quantitation of metabolite content with proton magnetic resonance spectroscopy.
J Magn Reson Imag
1999;
9:
711–716.
10.1002/(SICI)1522-2586(199905)9:5<711::AID-JMRI14>3.0.CO;2-3 CASPubMedWeb of Science®Google Scholar
- 32 Ross AJ, Sachdev PS, Wen W, Brodaty H. Longitudinal changes during aging using proton magnetic resonance spectroscopy. J Gerontol A Biol Sci Med Sci 2006; 61: 291–298.
- 33 Waldman AD, Rai GS. The relationship between cognitive impairment and in vivo metabolite ratios in patients with clinical Alzheimer's disease and vascular dementia: a proton magnetic resonance spectroscopy study. Neuroradiology 2003; 45: 507–512.
- 34 Dufouil C, Chalmers J, Coskun O, Besancon V, Bousser MG, Guillon P, MacMahon S, Mazoyer B, Neal B, Woodward M, Tzourio-Mazoyer N, Tzourio C, PROGRESS MRI Substudy Investigators. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation 2005; 112: 1644–1650.
- 35 Graham G, Blamire A, Howseman A, Rothman D, Fayad P, Brass L, Petroff O, Shulman R, Prichard J. Proton magnetic resonance spectroscopy of cerebral lactate and other metabolites in stroke patients. Stroke 1992; 23: 333–340.
- 36 Saunders DE, Howe FA, van den BA, McLean MA, Griffiths JR, Brown MM. Continuing ischemic damage after acute middle cerebral artery infarction in humans demonstrated by short-echo proton spectroscopy. Stroke 1995; 26: 1007–1013.
- 37 Graham G, Hwang J, Rothman D, Prichard J. Spectroscopic assessment of alterations in macromolecule and small molecule metabolites in human brain after stroke. Stroke 2001; 32: 2797–2802.