Clinical Psychopharmacology and Neuroscience 2017; 15(3): 243-247  https://doi.org/10.9758/cpn.2017.15.3.243
Improvement of Visuo-spatial Function Assessed by Raven’s Colored Progressive Matrices in Dementia with Lewy Bodies by Donepezil Treatment
Yuta Yoshino1, Takaaki Mori1, Taku Yoshida1, Yasutaka Toyota2, Hideaki Shimizu1, Jun-ichi Iga1, Shusaku Nishitani2, and Shu-ichi Ueno1
1Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Toon, Japan, 2Department of Neuropsychiatry, Zaidan Niihama Hospital, Niihama, Japan
Correspondence to: Takaaki Mori, MD, PhD, Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan, Tel: +82-81-89-960-5315, Fax: +82-81-89-960-5317, E-mail: taka960mori@gmail.com
Received: October 24, 2016; Revised: December 8, 2016; Accepted: December 20, 2016; Published online: August 31, 2017.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Objective

Donepezil is used to improve cognitive impairment of dementia with Lewy bodies (DLB). Visuo-spatial dysfunction is a well-known symptom of DLB. Non-verbal Raven’s Colored Progressive Matrices (RCPM) were used to assess both visual perception and reasoning ability in DLB subjects treated with donepezil.

Methods

Twenty-one DLB patients (mean age, 78.7±4.5 years) were enrolled. RCPM assessment was performed at the time of starting donepezil and within one year after starting donepezil.

Results

There were significant improvements of RCPM in the total scores between one year donepezil treatment (p=0.013), in both Set A score (p=0.002) and Set AB score (p=0.015), but trend in the Set B score (p=0.083).

Conclusion

Donepezil is useful for improving visuo-spatial impairment in DLB, but not for problem-solving impairment.

Keywords: Lewy body dementia, Cholinesterase inhibitors, Raven’s Colored Progressive Matrices, Visual spatial processing
INTRODUCTION

Dementia with Lewy bodies (DLB) is the second most common neurocognitive disorder next to Alzheimer’s disease (AD),1) and it is characterized by complex visual hallucinations, progressive cognitive dysfunction, and parkinsonism.2) Visual hallucination is one of the core features of DLB, present in 54% to 70% of DLB patients,3) and is one of the factors that increases caregiver burden.4) It has been reported that the visual hallucinations of DLB are caused by visuo-spatial, visuo-perceptual, or attention deficits.5)

Cholinesterase inhibitors such as donepezil have been used to treat cognitive dysfunction and neuropsychiatric symptoms.6) Several reports have shown that donepezil improves the symptoms associated with progressive cognitive dysfunction.7,8) In addition, imaging studies have reported that donepezil also improves visual hallucinations.9,10) On the other hand, it is well known that visuospatial deficits are worse in DLB than in AD.8,11,12) Cholinergic dysfunction in DLB is reported to be related to visual responses in the visual cortex.13,14)

The non-verbal Raven’s Colored Progressive Matrices (RCPM) test is a psychological tool used to assess both visual perception and reasoning ability.15) The RCPM score is not affected by various physical disabilities such as aphasia, cerebral palsy, and deafness.16) The RCPM score was reported to be lower in DLB than in AD in one observational study.17)

From these, visuo-spatial function of DLB is impaired and is possible to be improved by cholinesterase inhibitors. To the best of our knowledge, there are no longitudinal studies of how donepezil affects visuo-spatial deficits assessed by RCPM in DLB subjects. The present study examined how donepezil affects visuo-spatial function, as assessed by RCPM, in DLB subjects.

METHODS

Subjects

Untreated DLB patients (n=21; mean age, 78.7±4.5 years) who were outpatients at Ehime University Hospital and Zaidan Niihama Hospital were enrolled. DLB subjects were diagnosed according to the diagnostic criteria for probable DLB2) and were living with at least one caregiver. Some patients had psychiatric symptoms, but they could receive neuropsychological tests. Demographic data of DLB subjects are shown in Table 1. All patients were right-handed and had no cerebral vascular lesions on head computed tomography or magnetic resonance imaging (MRI). Patients who had a past history of psychiatric disorders and severe cardiovascular disease were excluded. All participants were of unrelated Japanese origin and signed written, informed consent forms approved by the institutional ethics committees of Ehime University Graduate School of Medicine and Zaidan Niihama Hospital.

Evaluation of DLB Symptoms

Cognitive impairments were evaluated by the Mini-Mental State Examination (MMSE).18) The severity of dementia was assessed by the Clinical Dementia Rating (CDR). Neuropsychiatric symptoms were evaluated by the neuropsychiatric inventory (NPI) assessed by caregivers.19) We explained the method of RCPM to the participants and started the examination after they understood and concentrated it. The visuospatial deficit was evaluated by the RCPM.15) These clinical data are also shown in Table 1.

Study Protocol

MMSE, CDR, NPI, and RCPM assessments were performed at the time of starting donepezil, and post prescribing RCPM was evaluated within one year after starting donepezil.

Statistical Analysis

Statistical analyses were performed using IBM SPSS Statistics ver 22.0 software (IBM Japan, Tokyo, Japan). Comparisons of pre and post RCPM scores (total, Set A, AB, and B) were conducted by the Wilcoxon signed-rank test. Linear regression analyses were performed to ascertain whether age, age of onset, educational years, duration of illness, dose of donepezil, mean administration period (week), change of drugs without donepezil between pre and post RCPM test, MMSE, improved MMSE score, NPI, and CDR were associated with improved RCPM scores (total, Set A, AB, and B). Statistical significance was defined at the 95% level (p=0.05).

RESULTS

Comparisons between Pre- and Post-RCPM Scores

There were significant improvements in the RCPM total score (p=0.013, Fig. 1A), Set A (p=0.002, Fig. 1B), and Set AB (p=0.015, Fig. 1C), but not in Set B (p=0.083, Fig. 1D). The details of the RCPM scores are shown in Table 2. The cut-off score of total RCPM score is 24/25 in Japanese version.20) According to this cut-off score, most patients had visuo-spatial dysfunction when pre RCPM test was conducted. The mean donepezil dose was 5.1±1.8 mg, and the mean administration period was 21.1±12.4 weeks. Some DLB subjects took other medications in pre-test (antipsychotics, one; antidepressants, two) and post-test (antipsychotics, three; antidepressants, two; antiparkinson drugs, two).

Linear Regression Analyses

Age, age of onset, educational years, duration of illness, dose of donepezil, mean administration period, change of drugs without donepezil between pre and post RCPM test, MMSE, improved MMSE score, NPI, and CDR were not significantly associated with improved RCPM scores for total, Set A, Set AB, and Set B scores.

DISCUSSION

The results of the present study show that donepezil may improve RCPM scores in DLB subjects. Interestingly, Set A and Set AB scores were significantly improved, but not Set B scores. From linear regression analysis, the improvement was not associated with age, age of onset, duration of illness, dose of donepezil, MMSE, NPI, or CDR.

Let us first examine the improvements of the RCPM scores in detail. In the previous study, identity, similarity, and difference in Set A constitute the main relational features of the elements. In Set AB, spatial orientation such as symmetry or location is the predominant theme, while both logical and spatial principles in Set B are involved in figure construction.21) It appears that donepezil improves mainly spatial orientation involved with identity, similarity, and difference, which constitute the main relational features of elements in DLB subjects. However, logical thinking about spatial features was not improved by donepezil treatment. According to the study that divided the RCPM elements into visuo-spatial and problem-solving impairment,22) visuo-spatial impairment was improved, but problem-solving impairment was not improved by donepezil in the present study. Actually, Saumier et al.23) reported that the domains of visual-spatial motor abilities were improved by donepezil in AD subjects.

Second, let us examine the improvement of visuo-spatial function by donepezil. Anatomically, posterior cortical atrophy leads to visual-spatial dysfunction. A rodent study suggested that the pharmacological activation of acetylcholine receptors relates to the visual response.24) Cerami et al.25) using [18F]FDG-positron emission tomography (PET) and diffusion tensor imaging-MRI, reported that the occipital-parietal-frontal network could be at the basis of visuo-perceptual and visuo-spatial integration. It was reported that DLB is associated with cholinergic dysfunction on PET using radiolabeled acetylcholine analogues.26) In that study, the deficit was in the posterior cortical regions, the inferior temporal gyrus, the supramarginal gyrus, and the posterior cingulate. Tiraboschi et al.27) reported that cholinergic dysfunction is more marked in DLB than in AD. In addition, cerebral blood flow in the occipital cortex is increased by donepezil.9) From these studies, we assumed that visuo-spatial function was improved through the increased cerebral blood flow in the occipital cortex with donepezil treatment.

This study had several limitations. One limitation is that there may have been Type II error due to the small sample size. In addition, the effect of other medications could not be considered sufficiently due to small sample size. Second is that cognitive fluctuation of DLB was not assessed when conducting the RCPM test. Cognitive fluctuation is a well-known symptom in DLB, and it also has a significant effect on cognitive function and activities of daily living in DLB patients and causes an increased care burden for caregivers.28) Cognitive fluctuation may have affected the RCPM scores in the present study. In future studies, RCPM scores should be evaluated at the same time as cognitive fluctuation in a large sample. Third is that we did not recruit the control arm without donepezil. In future study, it is need to evaluate the improvement of RCPM scores with donepezil compared to control subjects without donepezil. Lastly, Ikeda et al.29) reported that MMSE score significantly improved compared to placebo in the 10-mg group, but not in 5-mg group. We had to increase the dose of donepezil because of the evidence of Ikeda et al.29) Even with low dose, the subjects showed significant improvement with donepezil treatment. The donepezil dose of DLB patients in this study is 5.1±1.8. It is possible that higher dose of donepezil improve visuospatial function.

Acknowledgments

The authors would like to thank the patients and family members who participated in this study and the staff of Zaidan Niihama Hospital, Ehime, Japan for understanding the purpose of this study. This work was partially supported by a Health and Labor Science Research Grant from the Japanese Ministry of Health, Labor and Welfare, a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and JSPS KAKENHI Grant Number 25861015.

Figures
Fig. 1. The non-verbal Raven’s Colored Progressive Matrices (RCPM) scores before and after taking donepezil. (A) Total score, (B) Set A score, (C) Set AB score, and (D) Set B score.
Tables

The demographic data and clinical data for DLB subjects

Characteristic DLB subject 
Subject (n)21
Sex (n), male:female6:15
Age (yr)78.7±4.5
Age of onset (yr)77.0±4.6
Duration of illness (yr) 1.7±1.4
Education (yr)9.4±2.1
MMSE total score20.2±6.1
NPI-10 total score19.3±20.8
CDR score (0:0.5:1:2)1:7:10:3

Values are presented as number only or mean±standard deviation. DLB, dementia with Lewy bodies; MMSE, Mini-Mental State Examination; NPI, neuropsychiatric inventory; CDR, Clinical Dementia Rating.

The change of non-verbal Raven’s Colored Progressive Matrices scores and Mini-Mental State Examination (MMSE)

Characteristic Before (A)After (B) Improved score (B − A) 
Total (n=21)17.1±7.821.3±6.54.2±5.8
Set A (n=21)7.4±2.89.0±2.41.6±2.0
Set AB (n=21)5.8±3.37.5±2.71.8±3.1
Set B (n=21)4.0±2.64.8±2.10.9±2.4
MMSE (n=16)19.7±6.421.9±6.22.2±3.7

Values are presented as mean±standard deviation.

References
  1. McKeith, IG, Galasko, D, Kosaka, K, Perry, EK, Dickson, DW, and Hansen, LA (1996). Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 47, 1113-1124.
    Pubmed CrossRef
  2. McKeith, IG, Dickson, DW, Lowe, J, Emre, M, O’Brien, JT, and Feldman, H (2005). Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 65, 1863-1872.
    Pubmed CrossRef
  3. Aarsland, D, Ballard, C, Larsen, JP, and McKeith, I (2001). A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson’s disease with and without dementia. Int J Geriatr Psychiatry. 16, 528-536.
    Pubmed CrossRef
  4. Galvin, JE, Duda, JE, Kaufer, DI, Lippa, CF, Taylor, A, and Zarit, SH (2010). Lewy body dementia: caregiver burden and unmet needs. Alzheimer Dis Assoc Disord. 24, 177-181.
    Pubmed KoreaMed CrossRef
  5. Mori, E, Ikeda, M, Kosaka, K, and Donepezil-DLB Study Investigators (2012). Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol. 72, 41-52.
    Pubmed KoreaMed CrossRef
  6. Matsunaga, S, Kishi, T, Yasue, I, and Iwata, N (2015). Cholinesterase inhibitors for Lewy body disorders: a meta-analysis. Int J Neuropsychopharmacol. 19, pyv086.
    Pubmed KoreaMed CrossRef
  7. Thomas, AJ, Burn, DJ, Rowan, EN, Littlewood, E, Newby, J, and Cousins, D (2005). A comparison of the efficacy of donepezil in Parkinson’s disease with dementia and dementia with Lewy bodies. Int J Geriatr Psychiatry. 20, 938-944.
    Pubmed CrossRef
  8. Mori, E, Shimomura, T, Fujimori, M, Hirono, N, Imamura, T, and Hashimoto, M (2000). Visuoperceptual impairment in dementia with Lewy bodies. Arch Neurol. 57, 489-493.
    Pubmed CrossRef
  9. Mori, T, Ikeda, M, Fukuhara, R, Nestor, PJ, and Tanabe, H (2006). Correlation of visual hallucinations with occipital rCBF changes by donepezil in DLB. Neurology. 66, 935-937.
    Pubmed CrossRef
  10. Satoh, M, Ishikawa, H, Meguro, K, Kasuya, M, Ishii, H, and Yamaguchi, S (2010). Improved visual hallucination by donepezil and occipital glucose metabolism in dementia with Lewy bodies: the Osaki-Tajiri project. Eur Neurol. 64, 337-344.
    Pubmed CrossRef
  11. Ala, TA, Hughes, LF, Kyrouac, GA, Ghobrial, MW, and Elble, RJ (2001). Pentagon copying is more impaired in dementia with Lewy bodies than in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 70, 483-488.
    Pubmed KoreaMed CrossRef
  12. Collerton, D, Burn, D, McKeith, I, and O’Brien, J (2003). Systematic review and meta-analysis show that dementia with Lewy bodies is a visual-perceptual and attentional-executive dementia. Dement Geriatr Cogn Disord. 16, 229-237.
    Pubmed CrossRef
  13. Kimura, F, Fukuda, M, and Tsumoto, T (1999). Acetylcholine suppresses the spread of excitation in the visual cortex revealed by optical recording: possible differential effect depending on the source of input. Eur J Neurosci. 11, 3597-3609.
    Pubmed CrossRef
  14. Silver, MA, Shenhav, A, and D’Esposito, M (2008). Cholinergic enhancement reduces spatial spread of visual responses in human early visual cortex. Neuron. 60, 904-914.
    Pubmed KoreaMed CrossRef
  15. Raven, JC (1947). Colored progressive matrices sets A, AB, B. London: HK Lewis
  16. Spreen, O, and Staruss, E (1998). A compendium of neuropsychological tests: administration, norms, and commentary. Oxford: Oxford University Press
  17. Kawai, Y, Miura, R, Tsujimoto, M, Sakurai, T, Yamaoka, A, and Takeda, A (2013). Neuropsychological differentiation between Alzheimer’s disease and dementia with Lewy bodies in a memory clinic. Psychogeriatrics. 13, 157-163.
    Pubmed CrossRef
  18. Folstein, MF, Folstein, SE, and McHugh, PR (1975). “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician”. J Psychiatr Res. 12, 189-198.
    Pubmed CrossRef
  19. Cummings, JL, Mega, M, Gray, K, Rosenberg-Thompson, S, Carusi, DA, and Gornbein, J (1994). The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 44, 2308-2314.
    Pubmed CrossRef
  20. Sugishita, M, and Yamazaki, K (1993). Raven’s colored progressive matrices (in Japanese). Tokyo: Nihon Bunka Kagakusya
  21. Weichbold, V, and Herka, H (2003). Performance of hearing impaired children on Raven’s Coloured Progressive Matrices Test. Int J Pediatr Otorhinolaryngol. 67, 1213-1217.
    Pubmed CrossRef
  22. Ambra, FI, Iavarone, A, Ronga, B, Chieffi, S, Carnevale, G, and Iaccarino, L (2016). Qualitative patterns at Raven’s colored progressive matrices in mild cognitive impairment and Alzheimer’s disease. Aging Clin Exp Res. 28, 561-565.
    CrossRef
  23. Saumier, D, Murtha, S, Bergman, H, Phillips, N, Whitehead, V, and Chertkow, H (2007). Cognitive predictors of donepezil therapy response in Alzheimer disease. Dement Geriatr Cogn Disord. 24, 28-35.
    Pubmed CrossRef
  24. Soma, S, Shimegi, S, Suematsu, N, and Sato, H (2013). Cholinergic modulation of response gain in the rat primary visual cortex. Sci Rep. 3, 1138.
    Pubmed KoreaMed CrossRef
  25. Cerami, C, Crespi, C, Della Rosa, PA, Dodich, A, Marcone, A, and Magnani, G (2015). Brain changes within the visuo-spatial attentional network in posterior cortical atrophy. J Alzheimers Dis. 43, 385-395.
  26. Shimada, H, Hirano, S, Shinotoh, H, Aotsuka, A, Sato, K, and Tanaka, N (2009). Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology. 73, 273-278.
    Pubmed CrossRef
  27. Tiraboschi, P, Hansen, LA, Alford, M, Merdes, A, Masliah, E, and Thal, LJ (2002). Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry. 59, 946-951.
    Pubmed CrossRef
  28. Lee, DR, Taylor, JP, and Thomas, AJ (2012). Assessment of cognitive fluctuation in dementia: a systematic review of the literature. Int J Geriatr Psychiatry. 27, 989-998.
    Pubmed CrossRef
  29. Ikeda, M, Mori, E, Matsuo, K, Nakagawa, M, and Kosaka, K (2015). Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial. Alzheimers Res Ther. 7, 4.
    Pubmed KoreaMed CrossRef


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