Top

Alzheimer's Research & Therapy

Published in:

Open Access 01-12-2015 | Research

Hippocampal atrophy but not white-matter changes predicts the long-term cognitive response to cholinesterase inhibitors in Alzheimer’s disease

Authors: Yu-Wen Cheng, Ta-Fu Chen, Ting-Wen Cheng, Ya-Mei Lai, Mau-Sun Hua, Ya-Fang Chen, Ming-Jang Chiu

Published in: Alzheimer's Research & Therapy | Issue 1/2015

Abstract

Introduction

This study aimed to investigate the feasibility of predicting the long–term effects of cholinesterase inhibitors (ChEI) with common clinical neuroimaging parameters of Alzheimer’s disease, including medial temporal lobe atrophy (MTA) and white matter hyperintensity (WMH).

Method

A cohort of 353 patients with very mild to moderate Alzheimer’s disease received cholinesterase inhibitors and were followed for a median of 46.6 months. Baseline clinical data, including age, educational level, Clinical Dementia Rating (CDR), Taiwanese Mental State Examination (TMSE), and visual scoring for MTA and WMH were tested as possible predictive factors that influence the survival from a TMSE decline of at least 3 points.

Results

During the follow-up period, 162(46 %) patients had a significant TMSE decline. Patients with age-adjusted prominent MTA had a significantly shorter TMSE-decline free interval than those without (43.4 ± 4.5 months vs. 68.2 ± 9.5 months, log rank test p-value =0.001). However, the severity of WMH does not significantly influence cognitive outcomes. Cox regression analysis identified that younger age at the time of starting ChEI (p < 0.0005) and higher total MTA scores (p = 0.002) predict a more rapid TMSE decline under ChEI therapy.

Conclusions

Younger age at the time of starting ChEI and higher visual scoring of MTA may imply a more advanced Alzheimer’s pathology. WMH load is not a prognostic indicator of treatment response to ChEI.

Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;25:Cd005593. doi:10.1002/14651858.cd005593.

Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol. 2010;9:702–16. http://dx.doi.org/10.1016/S1474-4422(10)70119-8.CrossRefPubMed

Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, et al. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275:251–83. doi:10.1111/joim.12191.PubMedCentralCrossRefPubMed

Amar K, Wilcock GK, Scot M, Lewis T. The presence of leuko-araiosis in patients with Alzheimer’s disease predicts poor tolerance to tacrine, but does not discriminate responders from non-responders. Age Ageing. 1997;26:25–9.CrossRefPubMed

Tanaka Y, Hanyu H, Sakurai H, Shimizu S, Takasaki M. Characteristics of MRI features in Alzheimer’s disease patients predicting response to donepezil treatment. Nippon Ronen Igakkai Zasshi. 2003;40:261–6.CrossRefPubMed

Connelly PJ, Prentice NP, Fowler KG. Predicting the outcome of cholinesterase inhibitor treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2005;76:320–4. doi:10.1136/jnnp.2004.043539.PubMedCentralCrossRefPubMed

Connelly PJ, Prentice NP, Fowler KG. Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer’s disease. Int J Geriatr Psychiatry. 2005;20:623–8. doi:10.1002/gps.1331.CrossRefPubMed

Devine ME, Fonseca JA, Walker RW, Sikdar T, Stevens T, Walker Z. Cerebral white matter changes and rate of progression of dementia during cholinesterase inhibitor treatment: a retrospective cohort study. Int J Geriatr Psychiatry. 2007;22:1120–6. doi:10.1002/gps.1799.CrossRefPubMed

Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.CrossRefPubMed

10.

Jack Jr CR, Petersen RC, Xu YC, O’Brien PC, Smith GE, Ivnik RJ, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. 1999;52:1397–403.PubMedCentralCrossRefPubMed

11.

Korf ES, Wahlund LO, Visser PJ, Scheltens P. Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology. 2004;63:94–100.CrossRefPubMed

12.

Devanand DP, Pradhaban G, Liu X, Khandji A, De Santi S, Segal S, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology. 2007;68:828–36. doi:10.1212/01.wnl.0000256697.20968.d7.CrossRefPubMed

13.

Jack Jr CR, Petersen RC, Xu Y, O’Brien PC, Smith GE, Ivnik RJ, et al. Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology. 2000;55:484–9.PubMedCentralCrossRefPubMed

14.

Velayudhan L, Proitsi P, Westman E, Muehlboeck JS, Mecocci P, Vellas B, et al. Entorhinal cortex thickness predicts cognitive decline in Alzheimer’s disease. J Alzheimers Dis. 2013;33:755–66. doi:10.3233/jad-2012-121408.PubMed

15.

Black S, Gao F, Bilbao J. Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment. Stroke. 2009;40:S48–52. doi:10.1161/strokeaha.108.537704.CrossRefPubMed

16.

Jeerakathil T, Wolf PA, Beiser A, Massaro J, Seshadri S, D’Agostino RB, et al. Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke. 2004;35:1857–61. doi:10.1161/01.str.0000135226.53499.85.CrossRefPubMed

17.

Lo RY, Jagust WJ. Vascular burden and Alzheimer disease pathologic progression. Neurology. 2012;79:1349–55. doi:10.1212/WNL.0b013e31826c1b9d.PubMedCentralCrossRefPubMed

18.

Kandiah N, Chander RJ, Ng A, Wen MC, Cenina AR, Assam PN. Association between white matter hyperintensity and medial temporal atrophy at various stages of Alzheimer’s disease. Eur J Neurol. 2015;22:150–5. doi:10.1111/ene.12546.CrossRefPubMed

19.

Prasad K, Wiryasaputra L, Ng A, Kandiah N. White matter disease independently predicts progression from mild cognitive impairment to Alzheimer’s disease in a clinic cohort. Dement Geriatr Cogn Disord. 2011;31:431–4. doi:10.1159/000330019.CrossRefPubMed

20.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS‐ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology. 1984;34:939–44. doi:10.1212/wnl.34.7.939.CrossRefPubMed

21.

Yip PK, Shyu YI, Liu SI, Lee JY, Chou CF, Chen RC. An epidemiological survey of dementia among elderly in an urban district of Taipei. Acta Neurol Sin. 1992;1:347–54.

22.

Shyu YI, Yip PK. Factor structure and explanatory variables of the Mini-Mental State Examination (MMSE) for elderly persons in Taiwan. J Formos Med Assoc. 2001;100:676–83.PubMed

23.

Scheltens P, Leys D, Barkhof F, Huglo D, Weinstein HC, Vermersch P, et al. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry. 1992;55:967–72.PubMedCentralCrossRefPubMed

24.

Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol. 1987;149:351–6. doi:10.2214/ajr.149.2.351.CrossRefPubMed

25.

Duara R, Loewenstein DA, Shen Q, Barker W, Varon D, Greig MT, et al. The utility of age-specific cut-offs for visual rating of medial temporal atrophy in classifying Alzheimer’s disease. MCI and cognitively normal elderly subjects. Front Aging Neurosci. 2013;5:47. doi:10.3389/fnagi.2013.00047.PubMedCentralCrossRefPubMed

26.

Duara R, Loewenstein DA, Potter E, Appel J, Greig MT, Urs R, et al. Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease. Neurology. 2008;71:1986–92. doi:10.1212/01.wnl.0000336925.79704.9f.PubMedCentralCrossRefPubMed

27.

Radanovic M, Pereira FR, Stella F, Aprahamian I, Ferreira LK, Forlenza OV, et al. White matter abnormalities associated with Alzheimer’s disease and mild cognitive impairment: a critical review of MRI studies. Expert Rev Neurother. 2013;13:483–93. doi:10.1586/ern.13.45.CrossRefPubMed

28.

Behl P, Bocti C, Swartz RH, Gao F, Sahlas DJ, Lanctot KL, et al. Strategic subcortical hyperintensities in cholinergic pathways and executive function decline in treated Alzheimer patients. Arch Neurol. 2007;64:266–72. doi:10.1001/archneur.64.2.266.CrossRefPubMed

29.

Yoshita M, Fletcher E, Harvey D, Ortega M, Martinez O, Mungas DM, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology. 2006;67:2192–8. doi:10.1212/01.wnl.0000249119.95747.1f.PubMedCentralCrossRefPubMed

30.

van Straaten EC, Harvey D, Scheltens P, Barkhof F, Petersen RC, Thal LJ, et al. Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia. J Neurol. 2008;255:1302–8. doi:10.1007/s00415-008-0874-y.PubMedCentralCrossRefPubMed

31.

Murray AD, Staff RT, Shenkin SD, Deary IJ, Starr JM, Whalley LT. Brain white matter hyperintensities: relative importance of vascular risk factor in non-demented elderly patients. Radiology. 2005;237:251–7. doi:10.1148/radiol.2371041496.CrossRefPubMed

32.

Kim H, Yun CH, Thomas RJ, Lee SH, Seo HS, Cho ER, et al. Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. Sleep. 2013;36:709–15. doi:10.5665/sleep.2632.PubMedCentralPubMed

33.

Karp A, Kareholt I, Qiu C, Bellander T, Winblad B, Fratiglioni L. Relation of education and occupation-based socioeconomic status to incident Alzheimer’s disease. Am J Epidemiol. 2004;159:175–83.CrossRefPubMed

34.

Sattler C, Toro P, Schonknecht P, Schroder J. Cognitive activity, education and socioeconomic status as preventive factors for mild cognitive impairment and Alzheimer’s disease. Psychiatry Res. 2012;196:90–5. doi:10.1016/j.psychres.2011.11.012.CrossRefPubMed

35.

Stern Y. Cognitive reserve and Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:S69–74.CrossRefPubMed

36.

Stern Y, Alexander GE, Prohovnik I, Mayeux R. Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer’s disease. Ann Neurol. 1992;32:371–5. doi:10.1002/ana.410320311.CrossRefPubMed

37.

Chiu MJ, Chen YF, Chen TF, Yang SY, Yang FP, Tseng TW, et al. Plasma tau as a window to the brain-negative associations with brain volume and memory function in mild cognitive impairment and early alzheimer’s disease. Hum Brain Mapp. 2014;35:3132–42. doi:10.1002/hbm.22390.CrossRefPubMed

38.

van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L, et al. Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke. 2006;37:836–40. doi:10.1161/01.str.0000202585.26325.74.CrossRefPubMed

Title: Hippocampal atrophy but not white-matter changes predicts the long-term cognitive response to cholinesterase inhibitors in Alzheimer’s disease
Authors: Yu-Wen Cheng
Ta-Fu Chen
Ting-Wen Cheng
Ya-Mei Lai
Mau-Sun Hua
Ya-Fang Chen
Ming-Jang Chiu
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Alzheimer's Research & Therapy / Issue 1/2015
Electronic ISSN: 1758-9193
DOI: https://doi.org/10.1186/s13195-015-0155-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Hippocampal atrophy but not white-matter changes predicts the long-term cognitive response to cholinesterase inhibitors in Alzheimer’s disease

Abstract

Introduction

Method

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Method

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial

Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography

Post-mortem analysis of neuroinflammatory changes in human Alzheimer’s disease

Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study

A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease

Microstate connectivity alterations in patients with early Alzheimer’s disease