Psychiatry Investig Search

CLOSE


Psychiatry Investig > Volume 14(5); 2017 > Article
Um, Kim, Jeong, Seo, Han, Hong, Lee, and Lim: Prediction of Treatment Response to Donepezil using Automated Hippocampal Subfields Volumes Segmentation in Patients with Mild Alzheimer's Disease

Abstract

Previous studies reported some relationships between donepezil treatment and hippocampus in Alzheimer's disease (AD). However, due to methodological limitations, their close relationships remain unclear. The aim of this study is to predict treatment response to donepezil by utilizing the automated segmentation of hippocampal subfields volumes (ASHS) in AD. Sixty four AD patients were prescribed with donepezil and were followed up for 24 weeks. Cognitive function was measured to assess whether there was a response from the donepezil treatment. ASHS was implemented on non-responder (NR) and responder (TR) groups, and receiver operator characteristic (ROC) analysis was conducted to evaluate the sensitivity, specificity, and accuracy of hippocampal subfields in predicting response to donepezil. The left total hippocampus and the CA1 area of the NR were significantly smaller than those of the TR group. The ROC curve analysis showed the left CA1 volumes showed highest area under curve (AUC) of 0.85 with a sensitivity of 88.0%, a specificity of 74.0% in predicting treatment response to donepezil treatment. We expect that hippocampal subfields volume measurements that predict treatment responses to current AD drugs will enable more evidence-based, individualized prescription of medications that will lead to more favorable treatment outcomes.

INTRODUCTION

Alzheimer's disease (AD) is a chronic and disabling disorder associated with substantial impairment, decreased quality of life in the older adults. As there is no treatment available which could modify the disease process, the mainstay of the treatment of AD has been symptomatic management using the acetylcholinesterase inhibitors (ChIEs) and glutamate antagonists.1 Among the ChIEs, the donepezil is used worldwide for cognitive and behavioral management of AD. Although the donepezil has been clinically recognized to stabilize cognition for 6 to 12 months, a large proportion of AD patients experience cognitive decline even after the initial intervention.2 Possibly the reason for these differences in treatment responsiveness are due to various factors such as racial, ethnic, genotype disparities, clinical stage of dementia, co-morbidities, concomitant medication, functional and structural neuronal substrates.2,3,4,5 However, fundamental reason for this variability is not well understood, but this is essential for understanding etiologies of AD and enhancing effective strategies for management of AD.
As the hippocampus is the core brain region playing a major role in memory function, its atrophy is frequently suggested as an important biomarker of AD trajectory. In this regard, a previous study showed reduced hippocampal volumes and deformations of the cornu ammonis region 1 region (CA1) and subiculum subfields were correlated with a poorer response to donepezil treatment.6 However, a longitudinal study did not prove the volumetric and shape change associated with treatment response of donepezil in AD patients.7 These might be attributable to small sample sizes and the methodological limitations of their analyses (3D surface mapping). Moreover, resemblance of hippocampus to a ‘Swiss roll’ hindered 3D surface mapping from delineating subtle differences between the subfields.8 To overcome the aforementioned methodological limitations, we used the subfield volume segmentation to elaborate the subtle changes of the hippocampus during the donepezil treatment in AD.

METHODS

Subjects

Sixty-four AD patients were recruited in this study. The inclusion criteria are as follows: 1) a diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association (NINCDS/ADRDA) criteria,9 2) a score on the Clinical Dementia Rating Scale (CDR)= 0.5 or 1.10 Subjects who had other neurological or psychiatric conditions and those taking any psychotropic medications were excluded. The study was approved by Institutional Review Board of the Catholic University of Korea. Written informed consent was obtained from all subjects and their guardians.

Donepezil treatment

Study participants were prescribed donepezil at a dose of 5 mg/day for the first 28 days; the dose was increased to 10 mg/day thereafter. After the 24-week study period, those who presented with 2 points or more improvement in Mini-Mental Status Examination (MMSE) from baseline were grouped as responders in the previous study.11

MRI acquisition

Imaging data were collected with a 3-Tesla Siemens Verio scanner located in the St. Vincent Hospital. The T1 weighted three dimensional magnetization prepared rapid gradient-echo (MPRAGE) sequences parameters were as follows: TE=2.5 ms; TR=1900 ms; inversion time (TI)=900 ms; flip angle (FA)= 9°; FOV=250×250 mm; matrix=256×256; and voxel size= 1.0×1.0×1.0 mm3. T2-weighted MRI sequences were as follows: TE=91 ms; TR=3700 ms; flip angle (FA)=150°; FOV= 220×220 mm; matrix=448×448 in plane resolution, and 3-mm slice thickness.

Hippocampal subfield volumes segmentation

Segmentation of the hippocampal subfields was performed with the ASHS (http://www.nitrc.org/projects/ashs/). This method uses a combination of a multi-atlas image segmentation algorithm and a learning-based bias correction technique.12 Each subject's T2-weighted image was registered to a set of manually labeled atlases with deformable registration, and the candidate segmentations provided by the atlas package were combined into a single consensus segmentation based on similarity-weighted voting. Finally, the corrective learning classifiers trained to detect the voxels mislabeled by the above approach were applied to the consensus segmentation. The following subfields were defined: cornu ammonis 1 region (CA1), 2 region (CA2), 3 region (CA3), 4 region (CA4), dentate gyrus (DG), and subiculum (SUB).

Statistical analysis

Descriptive statistics were performed using demographic and clinical scores from the neuropsychological tests. Student t-tests were used to assess statistical differences of continuous variables, and Chi-square tests were used to assess dichotomous variables of the treatment responder group and the non responder group.
In line with other volumetric analyses, raw volumes of each hippocampal subfield and the whole hippocampus (corresponding to the sum of the three subfields) were normalized by the total intracranial volume (TIV) to account for inter-individual variability in head size (normalized volume=1000× raw volume/TIV). Binary logistic regression with receiver operator characteristic (ROC) analysis was implemented to assess the sensitivity, specificity, and accuracy of hippocampal subfields to predict treatment response to donepezil treatment with the age, gender and education as covariates All statistical analyses were conducted with the use of the MedCalc for Windows, version 15.0 (MedCalc Software, Ostend, Belgium).

RESULTS

Demographic data

After 24 weeks donepezil treatment, the 38 (59.3%) study participants who showed response were classified as the treatment responder (TR) group. The other 26 (40.7%) subjects were classified as the treatment non-responder (NR) group. There were no significant baseline demographic and clinical characteristics between the TR group and the NR group. However, score changes of MMSE from baseline to 24 weeks were significantly different between TR group and NR group.

Hippocampal subfields volumes segmentation

The hippocampal subfields volumes of left total hippocampus and the CA1 area were significantly different between the TR group and the NR group (p<0.001) (Table 1). The ROC curve analysis showed the left CA1 volumes showed highest area under curve (AUC) of 0.85 with a sensitivity of 88.0%, a specificity of 74.0%, a positive predictive value (PPV) of 77.2% and a negative predictive value (NPV) of 86.0% (Figure 1). The left total hippocampus volume showed AUC value of 0.84 with a sensitivity of 86%, a specificity of 78.0%, a PPV of 79.6% and a NPV of 84.8% (Figure 1). However, the other regions of the left SUB, CA2, CA3 and all the right hippocampal subfields volumes could not reached the AUC >0.5.

DISCUSSION

To our knowledge, this is the first study of hippocampal subfield analysis in predicting treatment response to donepezil. According to our results, left total hippocampal volume and more significantly, left CA1 volume showed good validity in predicting response to donepezil. Regarding our results showing statistically significant association between left hippocampal volume and treatment response but not in the right hippocampal volume, a recent meta-analysis indicated that this asymmetry could be a state-dependent marker in AD.13
There have been numerous attempts to predict response to ChIEs. Digit symbol substitution test, medial temporal lobe atrophy and hippocampal structure change have all been purported to be potential predictors for ChIEs treatment.14,15,16,17 In our results, not only the left hippocampal volume but also, CA1 significantly predicted donepezil response, and this harbors several clinical implications. CA1 has been suggested to be a major target of neuronal loss in AD patients, and it was associated with the disease severity and duration.18,19 Previous animal studies proposed a possibility of close link between cholinergic modulation and CA1. Acetylcholine was crucial in maintaining long-term potntiation in CA1 region, consequently affecting synaptic plasticity of CA1 pyramidal neurons.20,21,22
Hippocampal subfield analysis has been frequently implemented to explore regional vulnerability of hippocampus in normal aging and AD patients.23,24,25,26,27,28,29 Indeed, many previous studies proposed disparate vulnerability of hippocampal subfield volumes to AD pathology, thus the importance of measuring subfield volumes rather than volume as a whole has been accentuated.25 Moreover, validity of measuring hippocampal volumes in foretelling of conversion from mild cognitive impairment to AD has been discussed.30,31 We believe our results are in line with the aforementioned studies, with possible implications of applying automated hippocampal subfield analysis in the monitoring of AD patients.
There are several limitations in our study that must be taken into consideration. First, inherent methodological limitations of neuroimaging and pertinent analytic methods are inevitable. Disparities in defining boundaries for hippocampal subfields can result in varying outcomes. Indeed, one study discussed differences in anatomical definition of hippocampal subfields, especially prominent in CA1.25 Second, our result 24-week design could be considered too short to reflect the treatment response of donepezil and resultant sustained changes in hippocampal volumes. However, a 24-week design has been frequently adopted to predict the treatment response of donepezil.32,33,34 One study with an identical design as our study indicated that 63% of donepezil-treated group showed improvement in cognition.33 Third, homogeneity of our study participants makes the results difficult to generalize.
In conclusion, we expect that hippocampal subfields volume measurements that predict treatment responses to current anti-dementia drugs will enable a more evidence-based, individualized prescription of medications that will lead to more favorable treatment outcomes.

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A1A02036578).

References

1. National Institute for Clinical Excellence (NICE). Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. Technology appraisal guidance. 2011. p.217.

2. Burns A, Yeates A, Akintade L, del Valle M, Zhang RY, Schwam EM, et al. Defining treatment response to donepezil in Alzheimer’s disease: responder analysis of patient-level data from randomized, placebo-controlled studies. Drugs Aging 2008;25:707-714. PMID: 18665662.
crossref pmid
3. Braga ILS, Silva PN, Furuya TK, Santos LC, Pires BC, Mazzotti DR, et al. Effect of APOE and CHRNA7 genotypes on the cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer’s disease. Am J Alzheimers Dis Other Dement 2015;30:139-144.
crossref
4. Perera G, Khondoker M, Broadbent M, Breen G, Stewart R. Factors associated with response to acetylcholinesterase inhibition in dementia: a cohort study from a secondary mental health care case register in London. PLoS One 2014;9:e109484. PMID: 25411838.
crossref pmid pmc
5. Zuckerman IH, Ryder PT, Simoni-Wastila L, Shaffer T, Sato M, Zhao L, et al. Racial and ethnic disparities in the treatment of dementia among medicare beneficiaries. J Gerontol B Psychol Sci Soc Sci 2008;63:S328S333.
crossref pdf
6. Csernansky JG, Wang L, Miller JP, Galvin JE, Morris JC. Neuroanatomical predictors of response to donepezil therapy in patients with dementia. Arch Neurol 2005;62:1718-1722. PMID: 16286546.
crossref pmid
7. Wang L, Harms MP, Staggs JM, Xiong C, Morris JC, Csernansky JG, et al. Donepezil treatment and changes in hippocampal structure in very mild Alzheimer disease. Arch Neurol 2010;67:99-106. PMID: 20065136.
crossref pmid pmc
8. Lim HK, Hong SC, Jung WS, Ahn KJ, Won WY, Hahn C, et al. Automated hippocampal subfield segmentation in amnestic mild cognitive impairments. Dement Geriatr Cogn Disord 2012;33:327-333. PMID: 22759884.
crossref pmid
9. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263-269. PMID: 21514250.
crossref pmid pmc
10. Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9(Suppl 1):173-176. PMID: 9447441.
crossref pmid
11. Wallin AK, Hansson O, Blennow K, Londos E, Minthon L. Can CSF biomarkers or pre-treatment progression rate predict response to cholinesterase inhibitor treatment in Alzheimer’s disease? Int J Geriatr Psychiatry 2009;24:638-647. PMID: 19123199.
crossref pmid
12. Yushkevich PA, Pluta JB, Wang H, Xie L, Ding SL, Gertje EC, et al. Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment. Hum Brain Mapp 2015;36:258-287. PMID: 25181316.
crossref pmid
13. Shi F, Liu B, Zhou Y, Yu C, Jiang T. Hippocampal volume and asymmetry in mild cognitive impairment and Alzheimer’s disease: metaanalyses of MRI studies. Hippocampus 2009;19:1055-1064. PMID: 19309039.
crossref pmid
14. Tanaka Y, Hanyu H, Sakurai H, Takasaki M, Abe K. Atrophy of the substantia innominata on magnetic resonance imaging predicts response to donepezil treatment in Alzheimer’s disease patients. Dement Geriatr Cogn Disord 2003;16:119-125. PMID: 12826736.
crossref pmid
15. Csernansky JG, Wang L, Miller J, Galvin JE, Morris JC. NEuroanatomical predictors of response to donepezil therapy in patients with dementia. Arch Neurol 2005;62:1718-1722. PMID: 16286546.
crossref pmid
16. Connelly PJ, Prentice NP, Fowler KG. Predicting the outcome of cholinesterase inhibitor treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2005;76:320-324. PMID: 15716519.
crossref pmid pmc
17. Kanetaka H, Hanyu H, Hirao K, Shimizu S, Sato T, Akai T, et al. Prediction of response to donepezil in Alzheimer’s disease: combined MRI analysis of the substantia innominata and SPECT measurement of ce rebral perfusion. Nucl Med Commun 2008;29:568-573. PMID: 18458605.
crossref pmid
18. Bobinski M, de Leon MJ, Tarnawski M, Wegiel J, Reisberg B, Miller DC, et al. Neuronal and volume loss in CA1 of the hippocampal formation uniquely predicts duration and severity of Alzheimer disease. Brain Res 1998;805:267-269. PMID: 9733982.
crossref pmid
19. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 1994;344:769-772. PMID: 7916070.
crossref pmid
20. Seeger T, Fedorova I, Zheng F, Miyakawa T, Koustova E, Gomeza J, et al. M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J Neurosci 2004;24:10117-10127. PMID: 15537882.
crossref pmid
21. Shinoe T, Matsui M, Taketo MM, Manabe T. Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. J Neurosci 2005;25:11194-11200. PMID: 16319319.
crossref pmid
22. Martin S, Clark R. The rodent hippocampus and spatial memory: from synapses to systems. Cell Mol Life Sci 2007;64:401-431. PMID: 17256090.
crossref pmid
23. Daugherty AM, Bender AR, Raz N, Ofen N. Age differences in hippocampal subfield volumes from childhood to late adulthood. Hippocampus 2016;26:220-228. PMID: 26286891.
crossref pmid
24. de Flores R, La Joie R, Chételat G. Structural imaging of hippocampal subfields in healthy aging and Alzheimer’s disease. Neuroscience 2015;309:29-50. PMID: 26306871.
crossref pmid
25. de Flores R, La Joie R, Landeau B, Perrotin A, Mézenge F, de La Sayette V, et al. Effects of age and Alzheimer’s disease on hippocampal subfields: comparison between manual and FreeSurfer volumetry. Human Brain Mapp 2015;36:463-474.
crossref
26. La Joie R, Perrotin A, de La Sayette V, Egret S, Doeuvre L, Belliard S, et al. Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer’s disease and semantic dementia. NeuroImage Clin 2013;3:155-162. PMID: 24179859.
crossref pmid pmc
27. Raz N, Daugherty AM, Bender AR, Dahle CL, Land S. Volume of the hippocampal subfields in healthy adults: differential associations with age and a pro-inflammatory genetic variant. Brain Struct Funct 2015;220:2663-2674. PMID: 24947882.
crossref pmid
28. Voineskos AN, Winterburn JL, Felsky D, Pipitone J, Rajji TK, Mulsant BH, et al. Hippocampal (subfield) volume and shape in relation to cognitive performance across the adult lifespan. Human Brain Mapp 2015;36:3020-3037.
crossref
29. Wisse LE, Biessels GJ, Heringa SM, Kuijf HJ, Koek DL, Luijten PR, et al. Hippocampal subfield volumes at 7T in early Alzheimer’s disease and normal aging. Neurobiol Aging 2014;35:2039-2045. PMID: 24684788.
crossref pmid
30. Csernansky JG, Wang L, Swank J, Miller JP, Gado M, McKeel D, et al. Preclinical detection of Alzheimer’s disease: hippocampal shape and volume predict dementia onset in the elderly. Neuroimage 2005;25:783792.

31. Khan W, Westman E, Jones N, Wahlund LO, Mecocci P, Vellas B, et al. Automated hippocampal subfield measures as predictors of conversion from mild cognitive impairment to alzheimer’s disease in two independent cohorts. Brain Topogr 2015;28:746-759. PMID: 25370484.
crossref pmid
32. Rogers S, Farlow M, Doody R, Mohs R, Friedhoff L. A 24-week, doubleblind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology 1998;50:136-145. PMID: 9443470.
crossref pmid
33. Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001;57:613-620. PMID: 11524468.
crossref pmid
34. Homma A, Imai Y, Tago H, Asada T, Shigeta M, Iwamoto T, et al. Donepezil treatment of patients with severe Alzheimer’s disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial. Dement Geriatr Cogn Disord 2008;25:399407.
crossref
Figure 1

(A) Segmentation scheme used for hippocampal subfields segmentation used in this study; (B) The predictive performances of baseline hippocampal subfields volume measurements in 24 weeks donepezil treatment in the patients with AD (C) Group differences of baseline hippocampal subfields volumes between the TR and the NR groups. AD: Alzheimer's disease, TR: treatment response, NR: treatment non-response, L-CA1: left cornu ammonis region 1 region, L-TOTALHIPP: left total hippocampus, L: left, R: right, TOT: total hippocampus, CA1: Cornu ammonis region 1, CA2: Cornu ammonis region 2, CA3: Cornu ammonis region 3, DG: dentate gyrus, SUB: subiculum.

pi-14-698-g001
Table 1

Demographic and clinical characteristics of study participants

pi-14-698-i001

TR: treatment responder, NR: treatment non-responder, SD: standard deviation, CDR: Clinical Dementia Rating, CDR-SB: CDR sum-ofbox, MMSE: Mini Mental Status Examination, ICV: intracranial volume



ABOUT
AUTHOR INFORMATION
ARTICLE CATEGORY

Browse all articles >

BROWSE ARTICLES
Editorial Office
#522, 27, Seochojungang-ro 24-gil, Seocho-gu, Seoul 06601, Korea
Tel: +82-2-537-6171    Fax: +82-2-537-6174    E-mail: kpa3355@kornet.net                

Copyright © 2018 by Korean Neuropsychiatric Association. All rights reserved.

Developed in M2community

Close layer
prev next