Aim: To determine whether 4 months of rivastigmine treatment would result in metabolic changes and whether metabolic changes correlate with changes in cognition in people with Alzheimer's disease (AD). Methods: Magnetic resonance spectra were acquired from the posterior cingulate cortex of subjects with AD at 3 T. Magnetic resonance imaging scans and cognitive tests were performed before and 4 months after the beginning of the treatment. Metabolite concentrations were quantified and used to calculate the metabolite ratios. Results: On average, the N-acetylaspartate/creatine (NAA/Cr) ratio decreased by 12.7% following 4 months of rivastigmine treatment, but changes in the NAA/Cr ratio correlated positively with changes in Mini-Mental State Examination scores. Conclusion: This positive correlation between changes in NAA/Cr and changes in cognitive performance suggests that the NAA/Cr ratio could be an objective indicator of a response to rivastigmine treatment. © 2014 S. Karger AG, Basel

Keywords:
Alzheimer’s disease, Cholinesterase inhibitor, Magnetic resonance spectroscopy, N-Acetylaspartate, Posterior cingulate, Rivastigmine
1.
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.
2.
Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer's disease. Am J Psychiatry 1984;141:1356-1364.
3.
Anthony JC, LeResche L, Niaz U, von Korff MR, Folstein MF: Limits of the ‘Mini-Mental State' as a screening test for dementia and delirium among hospital patients. Psychol Med 1982;12:397-408.
4.
Fox NC, Freeborough PA: Brain atrophy progression measured from registered serial MRI: validation and application to Alzheimer's disease. J Magn Reson Imaging 1997;7:1069-1075.
5.
Cuingnet R, Gerardin E, Tessieras J, Auzias G, Lehericy S, Habert MO, Chupin M, Benali H, Colliot O: Automatic classification of patients with Alzheimer's disease from structural MRI: a comparison of ten methods using the ADNI database. Neuroimage 2011;56:766-781.
6.
Fritzsche KH, Stieltjes B, Schlindwein S, van Bruggen T, Essig M, Meinzer HP: Automated MR morphometry to predict Alzheimer's disease in mild cognitive impairment. Int J Comput Assist Radiol Surg 2010;5:623-632.
7.
Jack CR Jr: Alliance for aging research AD biomarkers work group: structural MRI. Neurobiol Aging 2011;32(suppl 1):S48-S57.
8.
Jack CR Jr, Barkhof F, Bernstein MA, Cantillon M, Cole PE, Decarli C, Dubois B, Duchesne S, Fox NC, Frisoni GB, Hampel H, Hill DL, Johnson K, Mangin JF, Scheltens P, Schwarz AJ, Sperling R, Suhy J, Thompson PM, Weiner M, Foster NL: Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease. Alzheimers Dement 2011;7:474-485.e474.
9.
Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C, Madsen SK, Parikshak N, Hua X, Toga AW, Jack CR Jr, Weiner MW, Thompson PM: Validation of a fully automated 3D hippocampal segmentation method using subjects with Alzheimer's disease mild cognitive impairment, and elderly controls. Neuroimage 2008;43:59-68.
10.
Remy F, Mirrashed F, Campbell B, Richter W: Mental calculation impairment in Alzheimer's disease: a functional magnetic resonance imaging study. Neurosci Lett 2004;358:25-28.
11.
Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y: Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer's disease. Ann Neurol 1999;45:466-472.
12.
Sperling R, Chua E, Cocchiarella A, Rand-Giovannetti E, Poldrack R, Schacter DL, Albert M: Putting names to faces: successful encoding of associative memories activates the anterior hippocampal formation. Neuroimage 2003;20:1400-1410.
13.
Herholz K, Salmon E, Perani D, Baron JC, Holthoff V, Frolich L, Schonknecht P, Ito K, Mielke R, Kalbe E, Zundorf G, Delbeuck X, Pelati O, Anchisi D, Fazio F, Kerrouche N, Desgranges B, Eustache F, Beuthien-Baumann B, Menzel C, Schroder J, Kato T, Arahata Y, Henze M, Heiss WD: Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage 2002;17:302-316.
14.
Mosconi L: Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging 2005;32:486-510.
15.
Bohnen NI, Djang DS, Herholz K, Anzai Y, Minoshima S: Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature. J Nucl Med 2012;53:59-71.
16.
Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM, Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M, Mintun MA, Skovronsky DM: Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-ß plaques: a prospective cohort study. Lancet Neurol 2012;11:669-678.
17.
Herholz K, Ebmeier K: Clinical amyloid imaging in Alzheimer's disease. Lancet Neurol 2011;10:667-670.
18.
Laforce R Jr, Rabinovici GD: Amyloid imaging in the differential diagnosis of dementia: review and potential clinical applications. Alzheimers Res Ther 2011;3:31.
19.
Dougall NJ, Bruggink S, Ebmeier KP: Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia. Am J Geriatr Psychiatry 2004;12:554-570.
20.
Cummings JL: Alzheimer's disease. N Engl J Med 2004;351:56-67.
21.
Birks J: Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006:CD005593.
22.
Bartus RT, Dean RL 3rd, Beer B, Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science 1982;217:408-414.
23.
Camps P, Munoz-Torrero D: Cholinergic drugs in pharmacotherapy of Alzheimer's disease. Mini Rev Med Chem 2002;2:11-25.
24.
Li W, Antuono PG, Xie C, Chen G, Jones JL, Ward BD, Franczak MB, Goveas JS, Li SJ: Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment. Neuroimage 2012;60:1083-1091.
25.
Birks J, Grimley Evans J, Iakovidou V, Tsolaki M: Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev 2000:CD001191.
26.
Grossberg G, Irwin P, Satlin A, Mesenbrink P, Spiegel R: Rivastigmine in Alzheimer disease: efficacy over two years. Am J Geriatr Psychiatry 2004;12:420-431.
27.
Ritchie CW, Ames D, Clayton T, Lai R: Metaanalysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry 2004;12:358-369.
28.
Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M: Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 1999;318:633-638.
29.
Dhillon S: Spotlight on rivastigmine transdermal patch: in dementia of the Alzheimer's type. Drugs Aging 2011;28:927-930.
30.
Priano L, Gasco MR, Mauro A: Transdermal treatment options for neurological disorders: impact on the elderly. Drugs Aging 2006;23:357-375.
31.
Blesa R, Ballard C, Orgogozo JM, Lane R, Thomas SK: Caregiver preference for rivastigmine patches versus capsules for the treatment of Alzheimer disease. Neurology 2007;69(suppl 1):S23-S28.
32.
Bartha R, Smith M, Rupsingh R, Rylett J, Wells JL, Borrie MJ: High field (1)H MRS of the hippocampus after donepezil treatment in Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:786-793.
33.
Henigsberg N, Kalember P, Hrabac P, Rados M, Bajs M, Rados M, Kovavic Z, Loncar M, Madzar T: 1-H MRS changes in dorsolateral prefrontal cortex after donepezil treatment in patients with mild to moderate Alzheimer's disease. Coll Antropol 2011;35(suppl 1):S159-S162.
34.
Jessen F, Traeber F, Freymann K, Maier W, Schild HH, Block W: Treatment monitoring and response prediction with proton MR spectroscopy in AD. Neurology 2006;67:528-530.
35.
Krishnan KR, Charles HC, Doraiswamy PM, Mintzer J, Weisler R, Yu X, Perdomo C, Ieni JR, Rogers S: 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.
36.
Modrego PJ, Fayed N, Errea JM, Rios C, Pina MA, Sarasa M: Memantine versus donepezil in mild to moderate Alzheimer's disease: a randomized trial with magnetic resonance spectroscopy. Eur J Neurol 2010;17:405-412.
37.
Modrego PJ, Pina MA, Fayed N, Diaz M: Changes in metabolite ratios after treatment with rivastigmine in Alzheimer's disease: a nonrandomised controlled trial with magnetic resonance spectroscopy. CNS Drugs 2006;20:867-877.
38.
Penner J, Rupsingh R, Smith M, Wells JL, Borrie MJ, Bartha R: Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:104-110.
39.
Pouwels PJ, Frahm J: Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med 1998;39:53-60.
40.
Miller BL, Moats RA, Shonk T, Ernst T, Woolley S, Ross BD: Alzheimer disease: depiction of increased cerebral myo-inositol with proton MR spectroscopy. Radiology 1993;187:433-437.
41.
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.
42.
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.
43.
Schuff N, Amend D, Ezekiel F, Steinman SK, Tanabe J, Norman D, Jagust W, Kramer JH, Mastrianni JA, Fein G, Weiner MW: 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.
44.
Block W, Jessen F, Traber F, Flacke S, Manka C, Lamerichs R, Keller E, Heun R, Schild H: Regional N-acetylaspartate reduction in the hippocampus detected with fast proton magnetic resonance spectroscopic imaging in patients with Alzheimer disease. Arch Neurol 2002;59:828-834.
45.
Dixon RM, Bradley KM, Budge MM, Styles P, Smith AD: Longitudinal quantitative proton magnetic resonance spectroscopy of the hippocampus in Alzheimer's disease. Brain 2002;125:2332-2341.
46.
Kantarci K, Jack CR Jr, Xu YC, Campeau NG, O'Brien PC, Smith GE, Ivnik RJ, Boeve BF, Kokmen E, Tangalos EG, Petersen RC: Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: A 1H MRS study. Neurology 2000;55:210-217.
47.
Teipel SJ, Meindl T, Grinberg L, Grothe M, Cantero JL, Reiser MF, Moller HJ, Heinsen H, Hampel H: The cholinergic system in mild cognitive impairment and Alzheimer's disease: an in vivo MRI and DTI study. Hum Brain Mapp 2011;32:1349-1362.
48.
Vogt BA, Crino PB, Vogt LJ: Reorganization of cingulate cortex in Alzheimer's disease: neuron loss, neuritic plaques, and muscarinic receptor binding. Cereb Cortex 1992;2:526-535.
49.
Stewart DJ, MacFabe DF, Leung LW: Topographical projection of cholinergic neurons in the basal forebrain to the cingulate cortex in the rat. Brain Res 1985;358:404-407.
50.
Chetelat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron JC: Mild cognitive impairment: can FDG-PET predict who is to rapidly convert to Alzheimer's disease? Neurology 2003;60:1374-1377.
51.
Whitwell JL, Petersen RC, Negash S, Weigand SD, Kantarci K, Ivnik RJ, Knopman DS, Boeve BF, Smith GE, Jack CR Jr: Patterns of atrophy differ among specific subtypes of mild cognitive impairment. Arch Neurol 2007;64:1130-1138.
52.
Jack CR Jr, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC: 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain 2008;131:665-680.
53.
Hattori N, Abe K, Sakoda S, Sawada T: Proton MR spectroscopic study at 3 Tesla on glutamate/glutamine in Alzheimer's disease. Neuroreport 2002;13:183-186.
54.
Kantarci K, Petersen RC, Boeve BF, Knopman DS, Tang-Wai DF, O'Brien PC, Weigand SD, Edland SD, Smith GE, Ivnik RJ, Ferman TJ, Tangalos EG, Jack CR Jr: 1H MR spectroscopy in common dementias. Neurology 2004;63:1393-1398.
55.
Modrego PJ, Fayed N, Sarasa M: Magnetic resonance spectroscopy in the prediction of early conversion from amnestic mild cognitive impairment to dementia: a prospective cohort study. BMJ Open 2011;1:e000007.
56.
Petrella JR, Wang L, Krishnan S, Slavin MJ, Prince SE, Tran TT, Doraiswamy PM: Cortical deactivation in mild cognitive impairment: high-field-strength functional MR imaging. Radiology 2007;245:224-235.
57.
Kantarci K, Knopman DS, Dickson DW, Parisi JE, Whitwell JL, Weigand SD, Josephs KA, Boeve BF, Petersen RC, Jack CR Jr: Alzheimer disease: postmortem neuropathologic correlates of antemortem 1H MR spectroscopy metabolite measurements. Radiology 2008;248:210-220.
58.
Bartha R, Drost DJ, Menon RS, Williamson PC: Comparison of the quantification precision of human short echo time (1)H spectroscopy at 1.5 and 4.0 Tesla. Magn Reson Med 2000;44:185-192.
59.
Kantarci K, Reynolds G, Petersen RC, Boeve BF, Knopman DS, Edland SD, Smith GE, Ivnik RJ, Tangalos EG, Jack CR Jr: 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.
60.
Tkac I, Andersen P, Adriany G, Merkle H, Ugurbil K, Gruetter R: In vivo 1H NMR spectroscopy of the human brain at 7 T. Magn Reson Med 2001;46:451-456.
61.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J: The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44:2308-2314.
62.
Fisk JD, Beattie BL, Donnelly M: Ethical considerations for decision making for treatment and research participation. Alzheimers Dement 2007;3:411-417.
63.
Bartha R, Drost DJ, Menon RS, Williamson PC: Spectroscopic lineshape correction by QUECC: combined QUALITY deconvolution and eddy current correction. Magn Reson Med 2000;44:641-645.
64.
Kassem MN, Bartha R: Quantitative proton short-echo-time LASER spectroscopy of normal human white matter and hippocampus at 4 Tesla incorporating macromolecule subtraction. Magn Reson Med 2003;49:918-927.
65.
Bartha R, Drost DJ, Williamson PC: Factors affecting the quantification of short echo in-vivo 1H MR spectra: prior knowledge, peak elimination, and filtering. NMR Biomed 1999;12:205-216.
66.
Stanley JA, Drost DJ, Williamson PC, Thompson RT: The use of a priori knowledge to quantify short echo in vivo 1H MR spectra. Magn Reson Med 1995;34:17-24.
67.
Zhang Y, Brady M, Smith S: Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging 2001;20:45-57.
68.
Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM: FSL. Neuroimage 2012;62:782-790.
69.
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM: Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004;23(suppl 1):S208-S219.
70.
Woolrich MW, Jbabdi S, Patenaude B, Chappell M, Makni S, Behrens T, Beckmann C, Jenkinson M, Smith SM: Bayesian analysis of neuroimaging data in FSL. Neuroimage 2009;45(suppl 1):S173-S186.
71.
Wattmo C, Wallin AK, Londos E, Minthon L: Predictors of long-term cognitive outcome in Alzheimer's disease. Alzheimers Res Ther 2011;3:23.
72.
Kantarci K, Weigand SD, Petersen RC, Boeve BF, Knopman DS, Gunter J, Reyes D, Shiung M, O'Brien PC, Smith GE, Ivnik RJ, Tangalos EG, Jack CR Jr: Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 2007;28:1330-1339.
73.
Schott JM, Frost C, MacManus DG, Ibrahim F, Waldman AD, Fox NC: Short echo time proton magnetic resonance spectroscopy in Alzheimer's disease: a longitudinal multiple time point study. Brain 2010;133:3315-3322.
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2014
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