Article
The Relationship Between Medial Temporal Lobe Atrophy and Cognitive Impairment in Patients With Dementia With Lewy Bodies
Journal of Geriatric Psychiatry and Neurology 2015, Vol. 28(4) 249-254 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0891988715590210 jgpn.sagepub.com
Ryo Tagawa, MD, PhD1, Hiroshi Hashimoto, MD, PhD1, Aki Nakanishi, MD, PhD2, Youjirou Kawarada, MD, PhD2, Tomohiro Muramatsu, MD, PhD2, Yasunori Matsuda, MD, PhD1, Kouhei Kataoka, MD, PhD3, Aiko Shimada, MD, PhD1, Kentaro Uchida, MD1, Atsushi Yoshida, MD4, Shigeaki Higashiyama, MD, PhD4, Joji Kawabe, MD, PhD4, Toshihiro Kai, MD, PhD5, Susumu Shiomi, MD, PhD4, Hiroshi Mori, PhD6, and Koki Inoue, MD, PhD1
Abstract Background: The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans. Methods: Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment. Results: A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not. Conclusions: These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency. Keywords DLB, dementia, MRI, VSRAD advance, neuroimaging
Introduction
1
Dementia with Lewy bodies (DLB) is a neurodegenerative disorder based on diffuse Lewy body disease and a common cause of neurodegenerative dementia, second to Alzheimer disease (AD). The core clinical symptoms of DLB include cognitive fluctuations, recurrent visual hallucinations, and spontaneous features of Parkinsonism, and differ from the symptoms observed in patients with AD. However, the separation between DLB and AD remains a challenge clinically due to the clinical overlap of memory impairment between these diseases. Although the characteristic patterns of atrophy in patients with DLB have not yet established, recent studies using magnetic resonance imaging (MRI) have suggested that patients
Department of Neuropsychiatry, Graduate School of Medicine, Osaka City University, Osaka, Japan 2 Department of Neurology and Psychiatry, Osaka City Kousaiin Hospital, Osaka, Japan 3 Department of Psychiatry, Cocoroa Hospital, Osaka, Japan 4 Department of Nuclear Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan 5 Department of Psychiatry, Osaka City General Hospital, Osaka, Japan 6 Department of Neuroscience, Graduate School of Medicine, Osaka City University, Osaka, Japan
Received 6/19/2014. Received revised 3/5/2015. Accepted 3/10/2015. Corresponding Author: Ryo Tagawa, Department of Neuropsychiatry, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Email: [email protected]
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with DLB had less severe medial temporal lobe atrophy (MTA) than patients with AD,1,2 while the volume of the substantia innominata, hypothalamus,3 dorsal mesopontine gray matter,4,5 and amygdala was reduced.5 In contrast, MTA was previously shown to be similar in patients with DLB and normal individuals.3,6 The medial temporal lobe mainly constitutes the hippocampus, amygdala, and entorhinal cortex. Previous findings revealed that atrophic changes in the hippocampus or entorhinal cortex correlated with the severity of cognitive declines in patients with AD.7-9 Barber et al reported MTA correlated specifically with memory impairment in all patients with dementia, including DLB.6 Therefore, we hypothesized that the coexistence of AD pathology in patients with DLB may be associated with the development of MTA, thereby resulting in a close relationship between MTA and cognitive impairment, as well as in patients with AD. The voxel-based morphometry (VBM) method, which detects focal brain atrophy and enables us to quantify atrophy precisely, is useful in MRI studies on dementia.10 VBM can evaluate gray matter and white matter volume by voxel-byvoxel analysis. Furthermore, few studies have investigated the relationship between MTA and cognitive impairment in patients with DLB using VBM,11 although a significant relationship is often reported in patients with AD.7-9,12 Cognitive fluctuations are known to be a characteristic feature in DLB,1 and the findings of cognitive performance tests are influenced by transient changes in the cognitive function of patients. The voxel-based specific regional analysis system for AD (VSRAD) advance10 can automatically evaluate the severity of MTA from MRI scans and give an objective and quantitative index regardless of various clinical symptoms in patients with DLB. Therefore, in the present study, we investigated the relationship between MTA and cognitive impairment in patients with DLB using VSRAD advance.
Methods Participants Thirty-seven patients (11 men and 26 women) who were diagnosed with probable DLB were recruited from an outpatient clinic of the Department of Neurology and Neuropsychiatry in Osaka City Kousaiin Hospital between June 2006 and March 2011. The mean age of the patients was 80.5 years and the mean duration of dementia was 3.2 years. The clinical diagnosis of DLB was based on revised consensus criteria for the clinical and pathological diagnosis of the DLB guidelines.1 Other causes of dementia were excluded by laboratory investigations, including magnetic resonance or computed tomography imaging of the brain, an investigation of thyroid function, venereal disease research laboratory tests, and tests for vitamin B12 and folate. The Institutional Review Board of Osaka City University and the Osaka City Kousaiin Hospital approved this study protocol, and informed consent was obtained from each patient and his or her family representative after a detailed explanation of this study.
Functional and Behavioral Assessments Each patient underwent a clinical assessment before the MRI procedure. In order to assess the presence of cognitive impairment, Mini-Mental State Examination (MMSE)13 and the Revised Hasegawa Dementia Scale (HDS-R: from 0 to 30, with 0 being the most severe)14 were used while patients were mentally stable. The HDS-R14 has been used exclusively in East Asian countries as a screening test for dementia. The optimal cutoff scores of the HDS-R for mild dementia are 20/21 in Japan. The weight of the measures for memory was stronger than MMSE, and the measures for language were added.14 A previous study suggested that the HDS-R may be superior to MMSE as a cognitive screening test for AD.15
Magnetic Resonance Imaging Procedure All participants underwent an MRI study using a 1.5T Vision Plus imager (Gyroscan intera R8, Philips, the Netherlands). Axial, coronal, and sagittal T1-weighted sequence images (repetition time [TR], 500 ms; echo time [TE], 15.0 ms; 6 mm thickness) and axial T2-weighted sequence images (TR, 4000 ms; TE, 100 ms) were obtained for a diagnosis. The 3-dimensional volumetric acquisition of a T1-weighted gradient echo sequence produced a gapless series of thin sagittal sections using a magnetization-preparation rapid-acquisition gradient-echo sequence (TR, 10 ms; TE, 4.6 ms; flip angle, 10 , acquisition matrix, 256 256, 2.0-mm slice thickness).
Voxel-Based Specific Regional Analysis System For Alzheimer Disease Advance Procedure All MRI data were analyzed using VSRAD advance software.10 This software program, which run on Windows for VBM analysis with statistical parametric mapping 8 plus the Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL), was developed to discriminate patients with AD from healthy controls, as described subsequently.16 The MRIs were spatially normalized with only a 12-parameter affine transformation to the SPM template in order to correct for differences in brain size. These linearly transformed images were nonlinearly transformed and then modulated to the customized template for DARTEL, followed by smoothing using an 8-mm full width at half maximum kernel. The gray matter image of a patient was compared with the mean and standard deviation (SD) of gray matter images of healthy volunteers database, integrated into VSRAD advance, using voxel-by-voxel z-score analysis. The (small) z score is the volumetric indicator of each voxel, then acquired ðz score ¼ ðcontrol mean individual valueÞ=control SDÞ. Z-score maps were displayed by overlaying on tomographic sections and surface rendering of the standardized brain (Figure 1). The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala, which was impaired in the early stage of AD.10 In the present study, we used the (large) Z score is the
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Left medial
Right medial
Posterior
Anterior
Right lateral
Left lateral
Inferior
Superior
R
L
R
L
Figure 1. Z-score map of a 80-year-old woman with dementia with Lewy bodies (DLB). Colored areas indicating z-scores of >2.0 are overlaid as significantly atrophied regions on tomographic sections and cortical surface of the standardized magnetic resonance imaging (MRI) template. A target volume of interest (VOI) in the medial temporal lobe is demarcated with purple lines.
volumetric indicator of VOI, then acquired (Z score ¼ average positive z score in the target VOI). The higher the Z score, the more severe the atrophy in the target VOI in the medial temporal lobe.
Statistical Analysis Statistical analysis was performed with SPSS for Windows 19.0 (SPSS Japan, Tokyo, Japan). Spearman rank correlation coefficients were calculated between the Z score and the age of the patient, the onset age of the disease, duration of DLB, years of education, MMSE total scores, and the HDS-R total scores. We investigated the relationship between these other measures and subscores of MMSE and the HDS-R. Furthermore, to clarify whether the Z score correlated with cognitive impairment independent of variable clinical factors including sex, the age of the patient, the onset age of the disease, duration of DLB, years of education, and cholinesterase inhibitor (ChEI) treatment, stepwise multiple regression analysis was performed to examine the contribution or interactions between the Z score and MMSE total scores, the HDS-R total scores, and clinical
factors as independent variables. All statistical tests were two-tailed, with significance at P < .05.
Results The demographic results and general characteristics of the study samples are shown in Table 1. Nine patients received the ChEI treatment, which was only donepezil instead of galantamine or rivastigmine. A negative correlation was observed between the Z scores and MMSE total scores and the HDS-R total scores (P < .05). A correlation was not detected between the Z score and the age of the patients, onset age of the disease, duration of DLB, or years of education (Table 2). Correlations were observed between the Z score and the subscales for temporal orientation (P ¼ .007), place orientation (P ¼ .024), and recall of 3 words (P ¼ .041) of MMSE and the subscales for age (P ¼ .007), temporal orientation (P ¼ .014), recall of 3 words (P < .001), immediate recall of 5 objects (P < .001), and word fluency (P ¼ .016) of the HDS-R (Table 3). Stepwise multiple regression analysis, which was performed to adjust the covariate effects of sex, the age of the patient, the onset age of
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Table 1. General Characteristics of the Study Sample. N ¼ 37, Mean + SD 80.5 + 6.0 77.7 + 6.8 3.2 + 2.8 9.7 + 4.8 18.5 + 5.0 17.2 + 5.7 1.94 + 1.37 (9/28)
Age, years Onset age of the disease, years Duration of dementia, years Education, years MMSE total score HDS-R total score Z score Donepezil treatment (+)
Discussion
Abbreviations: MMSE, Mini-Mental State Examination; HDS-R, Revised Hasegawa Dementia Scale; SD, standard deviation.
Table 2. Spearman Correlations Between Z Score and Other Measures.
Age, years Onset age of the disease, years Duration of dementia, years Education, years MMSE total score HDS-R total score
Correlation Coefficient
P Value
0.288 0.206 0.210 0.193 0.433 0.663
.083 .221 .211 .252 .007 .001
Abbreviations: MMSE, Mini-Mental State Examination; HDS-R, Revised Hasegawa Dementia Scale.
Table 3. Spearman Correlations Between the Z Score and Subscores of MMSE and the HDS-R.a
MMSE Temporal orientation Place orientation Registration (words) Attention/calculation Recall of 3 words Language Naming watch and pen Following slang Following the three step Following order Writing one full sentence Visual construction HDS-R Question about the age Temporal orientation Place orientation Registration (words) Attention/caluculation Digit span backword Recall of 3 words Immediate recall of 5 objects Word fluency
the disease, duration of DLB, years of education, MMSE total scores, and donepezil treatment, revealed that the HDS-R total scores independently correlated with the Z score. Only 1 model, including the HDS-R total score as the only variable was calculated (b ¼ 0.560, F ¼ 16.0, R2 ¼ 0.294, P < .001) and was regarded as the best fitting model. The following regression equation described the relation between the Z score and the HDS-R total score; the Z-score ¼ 0:135 the HDSR total score þ 4:252.
Correlation Coefficient
P Value
0.434 0.370 – 0.162 0.337
.007 .024 – .338 .041
0.280 0.215 0.259 0.141 0.066 0.184
.093 .202 .122 .407 .696 .276
0.433 0.400 0.144 – 0.106 0.240 0.595 0.557 0.394
.007 .014 .396 – .531 .152 .001 .001 .016
Abbreviations: MMSE, Mini-Mental State Examination; HDS-R, Revised Hasegawa Dementia Scale. a Registration (words) of MMSE and the HDS-R was perfect scores in all patients, therefore correlation coefficients were not calculated.
The present study demonstrated that atrophy in entire regions of the hippocampus, entorhinal cortex, and amygdala was inversely related to the score of the cognitive performance test in patients with DLB using VSRAD advance. These results suggest that the degree of MTA may be associated with cognitive impairment in DLB. Few studies have investigated the relationship between MTA and the subscale scores of the cognitive performance test in patients with DLB.11 Watson et al reported that the Cambridge Cognitive Examination memory subscale score correlated with temporal lobe atrophy in DLB.11 We identified a relationship between MTA and the temporal and place orientation subscale scores, and the recall of 3 words subscale scores of both MMSE and the HDS-R in the present study. These results are consistent with previous findings and suggest a relationship between MTA and memory impairment in dementia.17 Moreover, in this study, the HDS-R total scores independently correlated with the Z score and extracted as the only variable as the model even adding MMSE total scores as covariate. The immediate recall of 5 objects and word fluency subscale scores of the HDS-R, which are the cognitive domains that the HDS-R stresses more weight on than MMSE, were correlated with MTA in DLB in this study.15 This may explain why the stepwise multiple regression analysis showed that the HDS-R total scores were the strongest independent variable that correlated with MTA in DLB. Most studies suggest that MTA contributes to the severity of cognitive impairment in patients with dementia.3,7-9,11,18 As far as DLB is concerned, several studies showed a correlation between MTA and cognitive impairment using MRI,6 however, few studies have investigated this relationship using VBM software.3,11 In the present study, we measured only one target VOI using the VSRAD advance.10 The software measured the degree of MTA in entire regions of the hippocampus, entorhinal cortex, and amygdala as a target VOI. The results of this study using VSRAD advance are consistent with previous findings using MRI. On the other hand, Whitwell et al found that grey matter atrophy in the dorsal midbrain and temporoparietal cortex correlated with cognitive impairment in DLB.3 Whitwell et al investigated focal brain atrophy in 72 patients with DLB, and the average total MMSE score was 22, compared with 72 patients with AD and 72 controls using VBM software.3 The inconsistencies between these results may have been caused by differences in the methods used, such as the
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manner used for placement of the target VOI, the severity of cognitive impairment in patients with DLB, or the various pathological backgrounds of the individual participants. Medial temporal lobe atrophy is a well-recognized feature of AD and is considered to be a highly accurate diagnostic marker for autopsy-confirmed AD.19 However, the feature is not specific for AD among dementia; it has also been detected in DLB, vascular dementia, Parkinson’s disease with dementia, and frontotemporal dementia.19 Previous studies have shown that patients with DLB have relative preservation of the medial temporal lobe when compared with AD.11,20 Moreover, recent studies suggested that DLB may be associated with severe focal atrophy, including the reduced dorsal mesopontine gray matter and amygdala volume.4,5 Nakatsuka et al reported that patients with DLB displayed specific white matter atrophy in the dorsal midbrain, dorsal pons, and cerebellum.21 These findings suggested that pure DLB shows various patterns of focal atrophy and MTA in dementia and is not directly related to Lewy body pathology. Further studies are needed to clarify the relationship between focal atrophy and cognitive impairment in DLB. Although the underlying pathological basis of MTA in DLB remains unclear, it could be closely related to the coexistence of AD pathology.19,22,23 Burton et al reported that hippocampal atrophy was a strong predictor of neurofibrillary tangles, the pathology of AD, and dorsal mesopontine grey matter atrophy was associated with Lewy body pathology in patients with DLB.19 Yavuz et al reported the hippocampal volumetry was sensitive in AD, which reflects the severity of the disease and could be used to support the diagnosis.7 The hippocampus itself may play an important role in memory and cognitive function, resulting in hippocampal atrophy in patients with AD which leads to memory and cognitive impairment. The VSRAD advance method enabled us to measure the degree of atrophy in regions related to AD. Therefore, our results suggest that the degree of the coexistence of AD pathology in MTA may also be correlated with cognitive impairment in patients with DLB. There are some limitations to this study. First, the sample size in this study was small and may not reflect a typical DLB population. Second, we cannot rule out the influence of the ChEI treatment, such as donepezil. The effects of ChEI in DLB remain unclear,24 however, that ChEI may have clinical effects on AD pathology in DLB. Mori et al reported that donepezil, one of ChEI, produced significant cognitive, behavioral, and global improvements.25 In Japan, donepezil was approved for the treatment of cognitive impairment in DLB. Although the ChEI treatment was not identified as an independent predictor in the multiple regression analysis performed in this study, we will have to examine the relationship in limited patients who take no ChEI to confirm our results. Third, these analyses did not consider interactions with atrophy in other brain areas. It is also possible that anatomically distant lesions contribute to cognitive impairment in DLB through a neural network. Therefore, we have to examine other regions that may be involved in cognitive function in DLB using other methods. Fourth, the results of MMSE or the HDS-R could not evaluate the precise degree of cognitive impairment due to clinical symptoms such
as cognitive fluctuations in DLB. Additionally, we cannot evaluate the impairment of visual function or attention, which are specific to DLB. Fifth, neuropathological confirmation was not performed in this study. Therefore, we cannot evaluate a-synuclein pathology of each patient. Several studies reported that a-synuclein pathology was associated with amygdala volume.26,27 Voxel-based specific regional analysis system for Alzheimer disease advance cannot evaluate the atrophy of hippocampus, amygdala, and entorhinal cortex, separately. We cannot rule out the influence of the a-synuclein on MTA. Finally, we cannot evaluate cerebrospinal markers. Additionally, VSRAD cannot measure the volume of whole brain. These parameters should be statistically investigated in the VBM study. Therefore, further studies using other instruments are needed to confirm our results. In conclusion, the results of the present study suggest that MTA is related to cognitive impairment in patients with DLB. The degree of MTA could contribute to the progression of cognitive impairment in patients with dementia, irrespective of the disease origin. The VSRAD advance method may be useful for grading cognitive dysfunction indirectly in DLB in clinical practice. We should investigate the relationship between cognitive impairment and MTA in patients with DLB in the longitudinal design. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Medical Research Foundation for Senile Dementia of Osaka.
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7. Yavuz BB, Ariogul S, Cankurtaran M, et al. Hippocampal atrophy correlates with the severity of cognitive decline. Int Psychogeriatr. 2007;19(4):767-777. 8. Nagata T, Shinagawa S, Ochiai Y, et al. Association between executive dysfunction and hippocampal volume in Alzheimer’s disease. Int Psychogeriatr. 2011;23(5):764-771. 9. Li X, Jiao J, Shimizu S, Jibiki I, Watanabe K, Kubota T. Correlations between atrophy of the entorhinal cortex and cognitive function in patients with Alzheimer’s disease and mild cognitive impairment. Psychiatry Clin Neurosci. 2012;66(7): 587-593. 10. Matsuda H, Mizumura S, Nemoto K, et al. Automatic voxel-based morphometry of structural MRI by SPM8 plus diffeomorphic anatomic registration through exponentiated lie algebra improves the diagnosis of probable Alzheimer disease. AJNR Am J Neuroradiol. 2012;33(6):1109-1114. 11. Watson R, O’Brien JT, Barber R, Blamire AM. Patterns of gray matter atrophy in dementia with Lewy bodies: a voxel-based morphometry study. Int Psychogeriatr. 2012;24(4):532-540. 12. Shim YS, Youn YC, Na DL, et al. Effects of medial temporal atrophy and white matter hyperintensities on the cognitive functions in patients with Alzheimer’s disease. Eur Neurol. 2011;66(2): 75-82. 13. 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(3):189-198. 14. Kim KW, Lee DY, Jhoo JH, et al. Diagnostic accuracy of minimental status examination and revised Hasegawa dementia scale for Alzheimer’s disease. Dement Geriatr Cogn Disord. 2005; 19(5-6):324-330. 15. Tsukamoto R, Akisaki T, Kuranaga M, Takata T, Yokono K, Sakurai T. Hasegawa Dementia Scale—revised, for screening of early Alzheimer’s disease in the elderly with type 2 diabetes. Geriatr Gerontol Int. 2009;9(2):213-215. 16. Tagawa R, Hashimoto H, Matsuda Y, et al. Correlation between right medial temporal lobe atrophy and persecutory delusions in patients with dementia of the Alzheimer’s type demonstrated on VSRAD advance. Osaka City Med J. 2014;60(2):73-80. 17. Tulving E, Markowitsch HJ. Episodic and declarative memory: role of the hippocampus. Hippocampus. 1998;8(3):198-204.
18. Bastos-Leite AJ, van der Flier WM, van Straaten EC, Staekenborg SS, Scheltens P, Barkhof F. The contribution of medial temporal lobe atrophy and vascular pathology to cognitive impairment in vascular dementia. Stroke. 2007;38(12):3182-3185. 19. Burton EJ, Barber R, Mukaetova-Ladinska EB, et al. Medial temporal lobe atrophy on MRI differentiates Alzheimer’s disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain. 2009;132(pt 1):195-203. 20. Hayashi H, Kawakatsu S, Suzuki A, et al. Application of the VSRAD, a specific and sensitive voxel-based morphometry, to comparison of entorhinal cortex atrophy between dementia with Lewy bodies and Alzheimer’s disease. Dement Geriatr Cogn Disord. 2012;34(5-6):328-331. 21. Nakatsuka T, Imabayashi E, Matsuda H, Sakakibara R, Inaoka T, Terada H. Discrimination of dementia with Lewy bodies from Alzheimer’s disease using voxel-based morphometry of white matter by statistical parametric mapping 8 plus diffeomorphic anatomic registration through exponentiated Lie algebra. Neuroradiology. 2013;55(5):559-566. 22. Fujishiro H, Iseki E, Higashi S, et al. Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia. Neurosci Lett. 2010;486(1):19-23. 23. Hansen L, Salmon D, Galasko D, et al. The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology. 1990;40(1):1-8. 24. Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cognitive impairment in Parkinson’s disease. Cochrane Database Syst Rev. 2012;3:CD006504. 25. Mori E, Ikeda M, Kosaka K, Donepezil DLBSI. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol. 2012;72(1):41-52. 26. Burton EJ, Mukaetova-Ladinska EB, Perry RH, Jaros E, Barber R, O’Brien JT. Neuropathological correlates of volumetric MRI in autopsy-confirmed Lewy body dementia. Neurobiol Aging. 2012;33(7):1228-1236. 27. Murray ME, Ferman TJ, Boeve BF, et al. MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies. Neurology. 2013;81(19):1681-1689.
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The Relationship Between Medial Temporal Lobe Atrophy and Cognitive Impairment in Patients With Dementia With Lewy Bodies
Journal of Geriatric Psychiatry and Neurology 2015, Vol. 28(4) 249-254 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0891988715590210 jgpn.sagepub.com
Ryo Tagawa, MD, PhD1, Hiroshi Hashimoto, MD, PhD1, Aki Nakanishi, MD, PhD2, Youjirou Kawarada, MD, PhD2, Tomohiro Muramatsu, MD, PhD2, Yasunori Matsuda, MD, PhD1, Kouhei Kataoka, MD, PhD3, Aiko Shimada, MD, PhD1, Kentaro Uchida, MD1, Atsushi Yoshida, MD4, Shigeaki Higashiyama, MD, PhD4, Joji Kawabe, MD, PhD4, Toshihiro Kai, MD, PhD5, Susumu Shiomi, MD, PhD4, Hiroshi Mori, PhD6, and Koki Inoue, MD, PhD1
Abstract Background: The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans. Methods: Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment. Results: A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not. Conclusions: These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency. Keywords DLB, dementia, MRI, VSRAD advance, neuroimaging
Introduction
1
Dementia with Lewy bodies (DLB) is a neurodegenerative disorder based on diffuse Lewy body disease and a common cause of neurodegenerative dementia, second to Alzheimer disease (AD). The core clinical symptoms of DLB include cognitive fluctuations, recurrent visual hallucinations, and spontaneous features of Parkinsonism, and differ from the symptoms observed in patients with AD. However, the separation between DLB and AD remains a challenge clinically due to the clinical overlap of memory impairment between these diseases. Although the characteristic patterns of atrophy in patients with DLB have not yet established, recent studies using magnetic resonance imaging (MRI) have suggested that patients
Department of Neuropsychiatry, Graduate School of Medicine, Osaka City University, Osaka, Japan 2 Department of Neurology and Psychiatry, Osaka City Kousaiin Hospital, Osaka, Japan 3 Department of Psychiatry, Cocoroa Hospital, Osaka, Japan 4 Department of Nuclear Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan 5 Department of Psychiatry, Osaka City General Hospital, Osaka, Japan 6 Department of Neuroscience, Graduate School of Medicine, Osaka City University, Osaka, Japan
Received 6/19/2014. Received revised 3/5/2015. Accepted 3/10/2015. Corresponding Author: Ryo Tagawa, Department of Neuropsychiatry, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Email: [email protected]
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with DLB had less severe medial temporal lobe atrophy (MTA) than patients with AD,1,2 while the volume of the substantia innominata, hypothalamus,3 dorsal mesopontine gray matter,4,5 and amygdala was reduced.5 In contrast, MTA was previously shown to be similar in patients with DLB and normal individuals.3,6 The medial temporal lobe mainly constitutes the hippocampus, amygdala, and entorhinal cortex. Previous findings revealed that atrophic changes in the hippocampus or entorhinal cortex correlated with the severity of cognitive declines in patients with AD.7-9 Barber et al reported MTA correlated specifically with memory impairment in all patients with dementia, including DLB.6 Therefore, we hypothesized that the coexistence of AD pathology in patients with DLB may be associated with the development of MTA, thereby resulting in a close relationship between MTA and cognitive impairment, as well as in patients with AD. The voxel-based morphometry (VBM) method, which detects focal brain atrophy and enables us to quantify atrophy precisely, is useful in MRI studies on dementia.10 VBM can evaluate gray matter and white matter volume by voxel-byvoxel analysis. Furthermore, few studies have investigated the relationship between MTA and cognitive impairment in patients with DLB using VBM,11 although a significant relationship is often reported in patients with AD.7-9,12 Cognitive fluctuations are known to be a characteristic feature in DLB,1 and the findings of cognitive performance tests are influenced by transient changes in the cognitive function of patients. The voxel-based specific regional analysis system for AD (VSRAD) advance10 can automatically evaluate the severity of MTA from MRI scans and give an objective and quantitative index regardless of various clinical symptoms in patients with DLB. Therefore, in the present study, we investigated the relationship between MTA and cognitive impairment in patients with DLB using VSRAD advance.
Methods Participants Thirty-seven patients (11 men and 26 women) who were diagnosed with probable DLB were recruited from an outpatient clinic of the Department of Neurology and Neuropsychiatry in Osaka City Kousaiin Hospital between June 2006 and March 2011. The mean age of the patients was 80.5 years and the mean duration of dementia was 3.2 years. The clinical diagnosis of DLB was based on revised consensus criteria for the clinical and pathological diagnosis of the DLB guidelines.1 Other causes of dementia were excluded by laboratory investigations, including magnetic resonance or computed tomography imaging of the brain, an investigation of thyroid function, venereal disease research laboratory tests, and tests for vitamin B12 and folate. The Institutional Review Board of Osaka City University and the Osaka City Kousaiin Hospital approved this study protocol, and informed consent was obtained from each patient and his or her family representative after a detailed explanation of this study.
Functional and Behavioral Assessments Each patient underwent a clinical assessment before the MRI procedure. In order to assess the presence of cognitive impairment, Mini-Mental State Examination (MMSE)13 and the Revised Hasegawa Dementia Scale (HDS-R: from 0 to 30, with 0 being the most severe)14 were used while patients were mentally stable. The HDS-R14 has been used exclusively in East Asian countries as a screening test for dementia. The optimal cutoff scores of the HDS-R for mild dementia are 20/21 in Japan. The weight of the measures for memory was stronger than MMSE, and the measures for language were added.14 A previous study suggested that the HDS-R may be superior to MMSE as a cognitive screening test for AD.15
Magnetic Resonance Imaging Procedure All participants underwent an MRI study using a 1.5T Vision Plus imager (Gyroscan intera R8, Philips, the Netherlands). Axial, coronal, and sagittal T1-weighted sequence images (repetition time [TR], 500 ms; echo time [TE], 15.0 ms; 6 mm thickness) and axial T2-weighted sequence images (TR, 4000 ms; TE, 100 ms) were obtained for a diagnosis. The 3-dimensional volumetric acquisition of a T1-weighted gradient echo sequence produced a gapless series of thin sagittal sections using a magnetization-preparation rapid-acquisition gradient-echo sequence (TR, 10 ms; TE, 4.6 ms; flip angle, 10 , acquisition matrix, 256 256, 2.0-mm slice thickness).
Voxel-Based Specific Regional Analysis System For Alzheimer Disease Advance Procedure All MRI data were analyzed using VSRAD advance software.10 This software program, which run on Windows for VBM analysis with statistical parametric mapping 8 plus the Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL), was developed to discriminate patients with AD from healthy controls, as described subsequently.16 The MRIs were spatially normalized with only a 12-parameter affine transformation to the SPM template in order to correct for differences in brain size. These linearly transformed images were nonlinearly transformed and then modulated to the customized template for DARTEL, followed by smoothing using an 8-mm full width at half maximum kernel. The gray matter image of a patient was compared with the mean and standard deviation (SD) of gray matter images of healthy volunteers database, integrated into VSRAD advance, using voxel-by-voxel z-score analysis. The (small) z score is the volumetric indicator of each voxel, then acquired ðz score ¼ ðcontrol mean individual valueÞ=control SDÞ. Z-score maps were displayed by overlaying on tomographic sections and surface rendering of the standardized brain (Figure 1). The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala, which was impaired in the early stage of AD.10 In the present study, we used the (large) Z score is the
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Left medial
Right medial
Posterior
Anterior
Right lateral
Left lateral
Inferior
Superior
R
L
R
L
Figure 1. Z-score map of a 80-year-old woman with dementia with Lewy bodies (DLB). Colored areas indicating z-scores of >2.0 are overlaid as significantly atrophied regions on tomographic sections and cortical surface of the standardized magnetic resonance imaging (MRI) template. A target volume of interest (VOI) in the medial temporal lobe is demarcated with purple lines.
volumetric indicator of VOI, then acquired (Z score ¼ average positive z score in the target VOI). The higher the Z score, the more severe the atrophy in the target VOI in the medial temporal lobe.
Statistical Analysis Statistical analysis was performed with SPSS for Windows 19.0 (SPSS Japan, Tokyo, Japan). Spearman rank correlation coefficients were calculated between the Z score and the age of the patient, the onset age of the disease, duration of DLB, years of education, MMSE total scores, and the HDS-R total scores. We investigated the relationship between these other measures and subscores of MMSE and the HDS-R. Furthermore, to clarify whether the Z score correlated with cognitive impairment independent of variable clinical factors including sex, the age of the patient, the onset age of the disease, duration of DLB, years of education, and cholinesterase inhibitor (ChEI) treatment, stepwise multiple regression analysis was performed to examine the contribution or interactions between the Z score and MMSE total scores, the HDS-R total scores, and clinical
factors as independent variables. All statistical tests were two-tailed, with significance at P < .05.
Results The demographic results and general characteristics of the study samples are shown in Table 1. Nine patients received the ChEI treatment, which was only donepezil instead of galantamine or rivastigmine. A negative correlation was observed between the Z scores and MMSE total scores and the HDS-R total scores (P < .05). A correlation was not detected between the Z score and the age of the patients, onset age of the disease, duration of DLB, or years of education (Table 2). Correlations were observed between the Z score and the subscales for temporal orientation (P ¼ .007), place orientation (P ¼ .024), and recall of 3 words (P ¼ .041) of MMSE and the subscales for age (P ¼ .007), temporal orientation (P ¼ .014), recall of 3 words (P < .001), immediate recall of 5 objects (P < .001), and word fluency (P ¼ .016) of the HDS-R (Table 3). Stepwise multiple regression analysis, which was performed to adjust the covariate effects of sex, the age of the patient, the onset age of
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Table 1. General Characteristics of the Study Sample. N ¼ 37, Mean + SD 80.5 + 6.0 77.7 + 6.8 3.2 + 2.8 9.7 + 4.8 18.5 + 5.0 17.2 + 5.7 1.94 + 1.37 (9/28)
Age, years Onset age of the disease, years Duration of dementia, years Education, years MMSE total score HDS-R total score Z score Donepezil treatment (+)
Discussion
Abbreviations: MMSE, Mini-Mental State Examination; HDS-R, Revised Hasegawa Dementia Scale; SD, standard deviation.
Table 2. Spearman Correlations Between Z Score and Other Measures.
Age, years Onset age of the disease, years Duration of dementia, years Education, years MMSE total score HDS-R total score
Correlation Coefficient
P Value
0.288 0.206 0.210 0.193 0.433 0.663
.083 .221 .211 .252 .007 .001
Abbreviations: MMSE, Mini-Mental State Examination; HDS-R, Revised Hasegawa Dementia Scale.
Table 3. Spearman Correlations Between the Z Score and Subscores of MMSE and the HDS-R.a
MMSE Temporal orientation Place orientation Registration (words) Attention/calculation Recall of 3 words Language Naming watch and pen Following slang Following the three step Following order Writing one full sentence Visual construction HDS-R Question about the age Temporal orientation Place orientation Registration (words) Attention/caluculation Digit span backword Recall of 3 words Immediate recall of 5 objects Word fluency
the disease, duration of DLB, years of education, MMSE total scores, and donepezil treatment, revealed that the HDS-R total scores independently correlated with the Z score. Only 1 model, including the HDS-R total score as the only variable was calculated (b ¼ 0.560, F ¼ 16.0, R2 ¼ 0.294, P < .001) and was regarded as the best fitting model. The following regression equation described the relation between the Z score and the HDS-R total score; the Z-score ¼ 0:135 the HDSR total score þ 4:252.
Correlation Coefficient
P Value
0.434 0.370 – 0.162 0.337
.007 .024 – .338 .041
0.280 0.215 0.259 0.141 0.066 0.184
.093 .202 .122 .407 .696 .276
0.433 0.400 0.144 – 0.106 0.240 0.595 0.557 0.394
.007 .014 .396 – .531 .152 .001 .001 .016
Abbreviations: MMSE, Mini-Mental State Examination; HDS-R, Revised Hasegawa Dementia Scale. a Registration (words) of MMSE and the HDS-R was perfect scores in all patients, therefore correlation coefficients were not calculated.
The present study demonstrated that atrophy in entire regions of the hippocampus, entorhinal cortex, and amygdala was inversely related to the score of the cognitive performance test in patients with DLB using VSRAD advance. These results suggest that the degree of MTA may be associated with cognitive impairment in DLB. Few studies have investigated the relationship between MTA and the subscale scores of the cognitive performance test in patients with DLB.11 Watson et al reported that the Cambridge Cognitive Examination memory subscale score correlated with temporal lobe atrophy in DLB.11 We identified a relationship between MTA and the temporal and place orientation subscale scores, and the recall of 3 words subscale scores of both MMSE and the HDS-R in the present study. These results are consistent with previous findings and suggest a relationship between MTA and memory impairment in dementia.17 Moreover, in this study, the HDS-R total scores independently correlated with the Z score and extracted as the only variable as the model even adding MMSE total scores as covariate. The immediate recall of 5 objects and word fluency subscale scores of the HDS-R, which are the cognitive domains that the HDS-R stresses more weight on than MMSE, were correlated with MTA in DLB in this study.15 This may explain why the stepwise multiple regression analysis showed that the HDS-R total scores were the strongest independent variable that correlated with MTA in DLB. Most studies suggest that MTA contributes to the severity of cognitive impairment in patients with dementia.3,7-9,11,18 As far as DLB is concerned, several studies showed a correlation between MTA and cognitive impairment using MRI,6 however, few studies have investigated this relationship using VBM software.3,11 In the present study, we measured only one target VOI using the VSRAD advance.10 The software measured the degree of MTA in entire regions of the hippocampus, entorhinal cortex, and amygdala as a target VOI. The results of this study using VSRAD advance are consistent with previous findings using MRI. On the other hand, Whitwell et al found that grey matter atrophy in the dorsal midbrain and temporoparietal cortex correlated with cognitive impairment in DLB.3 Whitwell et al investigated focal brain atrophy in 72 patients with DLB, and the average total MMSE score was 22, compared with 72 patients with AD and 72 controls using VBM software.3 The inconsistencies between these results may have been caused by differences in the methods used, such as the
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manner used for placement of the target VOI, the severity of cognitive impairment in patients with DLB, or the various pathological backgrounds of the individual participants. Medial temporal lobe atrophy is a well-recognized feature of AD and is considered to be a highly accurate diagnostic marker for autopsy-confirmed AD.19 However, the feature is not specific for AD among dementia; it has also been detected in DLB, vascular dementia, Parkinson’s disease with dementia, and frontotemporal dementia.19 Previous studies have shown that patients with DLB have relative preservation of the medial temporal lobe when compared with AD.11,20 Moreover, recent studies suggested that DLB may be associated with severe focal atrophy, including the reduced dorsal mesopontine gray matter and amygdala volume.4,5 Nakatsuka et al reported that patients with DLB displayed specific white matter atrophy in the dorsal midbrain, dorsal pons, and cerebellum.21 These findings suggested that pure DLB shows various patterns of focal atrophy and MTA in dementia and is not directly related to Lewy body pathology. Further studies are needed to clarify the relationship between focal atrophy and cognitive impairment in DLB. Although the underlying pathological basis of MTA in DLB remains unclear, it could be closely related to the coexistence of AD pathology.19,22,23 Burton et al reported that hippocampal atrophy was a strong predictor of neurofibrillary tangles, the pathology of AD, and dorsal mesopontine grey matter atrophy was associated with Lewy body pathology in patients with DLB.19 Yavuz et al reported the hippocampal volumetry was sensitive in AD, which reflects the severity of the disease and could be used to support the diagnosis.7 The hippocampus itself may play an important role in memory and cognitive function, resulting in hippocampal atrophy in patients with AD which leads to memory and cognitive impairment. The VSRAD advance method enabled us to measure the degree of atrophy in regions related to AD. Therefore, our results suggest that the degree of the coexistence of AD pathology in MTA may also be correlated with cognitive impairment in patients with DLB. There are some limitations to this study. First, the sample size in this study was small and may not reflect a typical DLB population. Second, we cannot rule out the influence of the ChEI treatment, such as donepezil. The effects of ChEI in DLB remain unclear,24 however, that ChEI may have clinical effects on AD pathology in DLB. Mori et al reported that donepezil, one of ChEI, produced significant cognitive, behavioral, and global improvements.25 In Japan, donepezil was approved for the treatment of cognitive impairment in DLB. Although the ChEI treatment was not identified as an independent predictor in the multiple regression analysis performed in this study, we will have to examine the relationship in limited patients who take no ChEI to confirm our results. Third, these analyses did not consider interactions with atrophy in other brain areas. It is also possible that anatomically distant lesions contribute to cognitive impairment in DLB through a neural network. Therefore, we have to examine other regions that may be involved in cognitive function in DLB using other methods. Fourth, the results of MMSE or the HDS-R could not evaluate the precise degree of cognitive impairment due to clinical symptoms such
as cognitive fluctuations in DLB. Additionally, we cannot evaluate the impairment of visual function or attention, which are specific to DLB. Fifth, neuropathological confirmation was not performed in this study. Therefore, we cannot evaluate a-synuclein pathology of each patient. Several studies reported that a-synuclein pathology was associated with amygdala volume.26,27 Voxel-based specific regional analysis system for Alzheimer disease advance cannot evaluate the atrophy of hippocampus, amygdala, and entorhinal cortex, separately. We cannot rule out the influence of the a-synuclein on MTA. Finally, we cannot evaluate cerebrospinal markers. Additionally, VSRAD cannot measure the volume of whole brain. These parameters should be statistically investigated in the VBM study. Therefore, further studies using other instruments are needed to confirm our results. In conclusion, the results of the present study suggest that MTA is related to cognitive impairment in patients with DLB. The degree of MTA could contribute to the progression of cognitive impairment in patients with dementia, irrespective of the disease origin. The VSRAD advance method may be useful for grading cognitive dysfunction indirectly in DLB in clinical practice. We should investigate the relationship between cognitive impairment and MTA in patients with DLB in the longitudinal design. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Medical Research Foundation for Senile Dementia of Osaka.
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