Abstract
Moyamoya disease is a cerebrovascular occlusive disease characterized by progressive stenosis or by occlusion at the terminal portion of the bilateral internal carotid arteries. The unusual vascular network (moyamoya vessels) at the base of the brain with this disease as collateral channels is developed in this disease. Social independence because of cognitive impairment has recently been recognized as an important unsolved social issue with adult moyamoya disease. The patients with cognitive impairment have difficulty in proving their status because the standard neuroradiological and neuropsychological methods to define cognitive impairment with moyamoya disease are not determined. These patients with cognitive impairment should be supported by social welfare as psychologically handicapped persons. Thus Cognitive Dysfunction Survey of the Japanese Patients with Moyamoya Disease (COSMO-JAPAN study) is planned. In this study, we want to establish a standard finding of the cognitive impairment in patients with moyamoya disease.
Keywords: moyamoya disease, cognitive dysfunction, [123I]iomazenil-single photon emission computed tomography, neuropsychological study
Introduction
Moyamoya disease is a cerebrovascular occlusive disease characterized by progressive stenosis or by occlusion at the distal ends of bilateral internal carotid arteries.1) The unusual vascular network (moyamoya vessels) at the base of the brain of individuals with this disease is considered to represent collateral channels formed as a result of progressive brain ischemic changes.1–3) The etiology of the disease is undefined. The findings that the incidence of the disease is highest in East Asian people and that the condition is frequently familial, suggest the involvement of a genetic factor in its pathogenesis.1) Extracranial-intracranial bypass surgery has been established as an effective neurosurgical intervention that increases cerebral blood flow (CBF) and prevents from ischemic attacks.4,5) However, difficulty with social independence accompanied by cognitive impairment has recently been recognized as an important unsolved social issue faced by patients with adult moyamoya disease.6–8) These patients are physically independent in daily life, but economically dependent. It is very difficult for them to obtain vocational skills because of cognitive impairment. These patients with cognitive impairment should be supported by social welfare as psychologically handicapped persons. They have difficulty in proving their status because the standard neuroradiological and neuropsychological methods to define cognitive impairment with moyamoya disease are not determined. Generally, cognitive impairment has been described as a neuropsychological disorder occurring after strokes that shows as disturbances in memory, attention, performance, and social behavioral disturbances mainly in pediatric cases.9,10) However, recent reports have focused on adult cases with neurocognitive impairment even without neuroradiological evidence of major stroke.8,11,12) Nakagawara et al.8) indicated that even if infarction has not yet occurred, brain dysfunction was associated with persistent hemodynamic compromise in the medial frontal lobes that can be visualized using [123I]iomazenil (IMZ)-single photon emission computed tomography (SPECT). This technique has the potential to become a tool for diagnosing cognitive impairment in adult moyamoya patients who do not show major abnormalities on computed tomography (CT) scans or magnetic resonance imaging (MRI). In addition, a common methodology for neuropsychological evaluation of these patients is yet to be determined.6,12,13) In this study, we want to establish the standard finding of the cognitive impairment in patients with moyamoya disease.
Materials and Methods
I. Methods/design
This is a prospective multicenter trial planning to analyze 60 patients with moyamoya disease. The study was approved by the Regional Ethical Review Board at Kyoto University (reference number: E-1754), and all patients will provide written informed consent before inclusion in the trial.
II. Inclusion and exclusion criteria
Inclusion criteria are as follows:
Male or female aged above 18 years under 60 years
Diagnosed as moyamoya disease or unilateral moyamoya disease on assessment by the neuroradiological committee14)
Without intracranial hemorrhage including intracerebral hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage
Without a large structural lesions (less than 1 cortical artery region) on neuroradiological studies
No neurological disorder influencing neuropsychological assessment, e.g., aphasia, hemianopsia, and agnosia
Modified Rankin scale ranging from 0 to 3
Without serious cognitive dysfunction assessed by subjective, objective symptoms, or daily life situation
Confirmation of informed consent
Exclusion criteria are as follows:
Quasi-moyamoya disease
Impossible to perform MRI
Assessment as unsuitable for this study
These criteria are also described in Table 1.
Table 1.
Inclusion and exclusion criteria
| Inclusion criteria |
|
| Exclusion criteria |
|
MRI: magnetic resonance imaging.
III. Background data
As background data of the patients, including in this study institute, sex, age, history of education, history of jobs, familial history, reason for diagnosis, modified Rankin scale, medication, and neurological deficits are recorded. In addition, blood sample is collected.
IV. SPECT
Brain N-isopropyl-p-123I-iodoamphetamine (123I-IMP) SPECT using QSPECT/dual table autoradiographic (ARG) method with three-dimensional stereotactic surface projection (3D-SSP) is performed to calculate the regional cerebral blood flow. To assess the regional cerebral vascular reserve, Diamox challenge SPECT is performed. The procedure for QSPECT/dual table ARG is described elsewhere in more detail.15,16) The data is analyzed by the SEE-JET (stereotactic extraction estimation based on the Japan EC-IC bypass trial study) program.17)
123I-IMZ-SPECT using QSPECT method with 3D-SSP is performed to assess cortical neuronal loss. Cortical neuron loss is analyzed using the SEE method (level 3: gyrus level) for 3D-SSP Z-score maps as previously reported.8)
V. MRI
MRI scans are also performed in all subjects. The scans are acquired on a 1.5 T or a 3 T scanner using a three-dimensional (3D) sagittal magnetization-prepared rapid gradient-echo imaging sequence, which is specially adjusted for the Japanese Alzheimer’s disease Neuroimaging Initiative (J-ADNI) 1/2 protocols. T1 structural sequences [3D MPRAGE on Siemens (Erlangen, Germany) and Philips Healthcare (Best, the Netherlands), 3D IR-SPGR on GE], FLAIR, T2WI (Dual Echo), T2*WI and TOF-MRA images are obtained in this study.18)
VI. Neuropsychological assessment
Basic cognitive ability is evaluated using the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) to assess intelligence, the Wechsler Memory Scale-Revised (WMS-R) to assess memory,19,20) and supplemental subtests for each task. Several frontal-functioning tests are also administered to detect specific neuropsychological deficits associated with adult moyamoya disease that co-occurs with difficulty in social independence. The Frontal Assessment Battery (FAB) tests general frontal cognitive ability. The Trail Making Test Part A (TMT-A) assesses speed of information processing,21,22) and the Trail Making Test Part B (TMT-B) and the Wisconsin Card Sorting Test (WCST) assess executive ability.5,18) Stroop test, Word-fluency test, and Frontal Systems Behavior Scale (FrSBe) are also used for frontal lobe function.22–24) The Beck Depression Inventory—Second Edition (BDI II) and State-Trait Anxiety Inventory (STAI) assess depressive state.26,27) In addition, WHOQOL26 assesses the quality of life. The item of neuroradiological and neuropsychological study is summarized in Table 2.28)
Table 2.
Neuroradiological and neuropsychological study
| Neuroradiological study |
| SPECT |
| 123I-IMP SPECT |
|
123I-IMZ-SPECT |
| MRI |
| MPRAGE/IR-SPGR |
| FLAIR |
| T2WI (Dual Echo) |
| T2*WI |
| TOF-MRA |
| Neuropsychological study |
| WAIS-III |
| WMS-R |
| FAB |
| WCST |
| Stroop test |
| Word-fluency |
| TMT A/B |
| BDI II |
| STAI |
| FrSBe |
| WHOQOL26 |
Discussion
Patients with moyamoya disease often suffer higher cognitive impairments such as memory, attention, and social behavioral disturbances.11–13) Such cognitive impairments may occur in patients with medial frontal lobe damage including the anterior cingulate cortex. However, confirmatory diagnosis of higher cognitive dysfunction in patients with moyamoya disease without obvious brain damages on CT or MRI imaging has not been established and could become a social issue.8)
In general, higher brain dysfunction associated with adult moyamoya disease could be detected by both neuropsychological findings and obvious medial frontal lobe damage detected by CT or MRI.11–13) In addition, hemodynamic ischemia in this region is analyzed by SPECT at rest and after Diamox challenge.15,16) More recently, loss of frontal cortical neuron could be estimated by functional neuroimaging using SPECT, because central benzodiazepine receptor mapping using 123I-IMZ is available for clinical use.8) IMZ is a specific radioactive tracer for the central benzodiazepine receptor that may be useful as a marker of cortical neuron loss. Recent work using IMZ-SPECT has demonstrated the association between cortical neuron loss in bilateral frontal medial cortices and cognitive dysfunction.8)
Neuropsychological analysis in patients with brain damage played an important role in the history of developing the research of brain function.13,19–22,29) Among brain dysfunction, higher cognitive dysfunction has been underestimated in the neurosurgical field. This dysfunction is often due to frontal lobe dysfunction. An extensive focus on frontal lobe function has not yet been taken by previous research regarding moyamoya disease. CBF and IMZ studies have shown that antero-medial frontal cortices fed by anterior circulation develop blood insufficiencies.8,30) For this reason, several neuropsychological test batteries to evaluate frontal lobe functioning in relation to hemodynamic compromise were employed for our preliminary study. Based on this preliminary study, we developed this study and adopted several tasks to examine the frontal lobe functions.11) To date, this is the first nation-wide survey of patients with moyamoya disease focusing on the neuroradiological and neuropsychological analysis in association with higher cognitive dysfunction. Patients with cognitive impairment should be supported by social welfare as psychologically handicapped persons.
The data obtained from the results of the study will play an important role in clarifying higher cognitive dysfunction in patients with moyamoya disease.
Appendix
I. COSMO-JAPAN study group
Kiyohiro Houkin, Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
Joji Nakagawara, Integrative Stroke Imaging Center, Department of Neurosurgery, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
Kuniaki Ogasawara, Department of Neurosurgery, Iwate Medical University, Morioka, Iwate, Japan
Teiji Tominaga, Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
Yoshikazu Okada, Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan
Tadashi Nariai, Department of Neurosurgery, Graduate School, Tokyo Medical and Dental University School of Medicine, Tokyo, Japan
Satoshi Kuroda, Department of Neurosurgery, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Toyama, Japan
Yukihiko Fujii, Department of Neurosurgery, Brain Research Institute, University of Niigata, Niigata, Niigata, Japan
Toshihiko Wakabayashi, Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Kazuo Yamada, Department of Neurosurgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
Susumu Miyamoto, Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan
Hiroyuki Nakase, Department of Neurosurgery, Nara Medical University, Nara, Nara, Japan
Koji Iihara, Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
Toshio Matsushima, Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Saga, Japan
Izumi Nagata, Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan
Toshiya Murai, Department of Psychiatry Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
Tomohisa Okada, Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan
Yasushi Takagi, Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan
II. Neuroradiological study committee
Joji Nakagawara, Integrative Stroke Imaging Center, Department of Neurosurgery, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
Tomohisa Okada, Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan
III. Neuropsychological study committee
Toshiya Murai, Department of Psychiatry Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
Takashi Nishikawa, Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino, Osaka, Japan
IV. Study protocol committee
Kuniaki Ogasawara, Department of Neurosurgery, Iwate Medical University, Morioka, Iwate, Japan
Toshio Matsushima, Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Saga, Japan
Yasushi Okada, Department of Cerebrovascular Medicine and Neurology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka, Japan
Yasushi Takagi, Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan
References
- 1). Suzuki J, Kodama N: Moyamoya disease—a review. Stroke 14: 104– 109, 1983 [DOI] [PubMed] [Google Scholar]
- 2). Hosoda Y, Ikeda E, Hirose S: Histopathological studies on spontaneous occlusion of the circle of Willis (cerebrovascular moyamoya disease). Clin Neurol Neurosurg 99( Suppl 2): S203– S208, 1997 [DOI] [PubMed] [Google Scholar]
- 3). Takekawa Y, Umezawa T, Ueno Y, Sawada T, Kobayashi M: Pathological and immunohistochemical findings of an autopsy case of adult moyamoya disease. Neuropathology 24: 236– 242, 2004 [DOI] [PubMed] [Google Scholar]
- 4). Houkin K, Kuroda S, Ishikawa T, Abe H: Neovascularization (angiogenesis) after revascularization in moyamoya disease. Which technique is most useful for moyamoya disease? Acta Neurochir (Wien) 142: 269– 276, 2000 [DOI] [PubMed] [Google Scholar]
- 5). Karasawa J, Kikuchi H, Furuse S, Kawamura J, Sakaki T: Treatment of moyamoya disease with STA-MCA anastomosis. J Neurosurg 49: 679– 688, 1978 [DOI] [PubMed] [Google Scholar]
- 6). Festa JR, Schwarz LR, Pliskin N, Cullum CM, Lacritz L, Charbel FT, Mathews D, Starke RM, Connolly ES, Marshall RS, Lazar RM: Neurocognitive dysfunction in adult moyamoya disease. J Neurol 257: 806– 815, 2010 [DOI] [PubMed] [Google Scholar]
- 7). Miyamoto S, Nagata I, Hashimoto N, Kikuchi H. Direct anastomotic bypass for cerebrovascular moyamoya disease. Neurol Med Chir (Tokyo) 38( Suppl): 294– 296, 1998 [DOI] [PubMed] [Google Scholar]
- 8). Nakagawara J, Osato T, Kamiyama K, Honjo K, Sugio H, Fumoto K, Murahashi T, Takada H, Watanabe T, Nakamura H: Diagnostic imaging of higher brain dysfunction in patients with adult moyamoya disease using statistical imaging analysis for [123I]iomazenil single photon emission computed tomography. Neurol Med Chir (Tokyo) 52: 318– 326, 2012 [DOI] [PubMed] [Google Scholar]
- 9). Matsushima Y, Aoyagi M, Masaoka H, Suzuki R, Ohno K: Mental outcome following encephaloduroarteriosynangiosis in children with moyamoya disease with the onset earlier than 5 years of age. Childs Nerv Syst 6: 440– 443, 1990 [DOI] [PubMed] [Google Scholar]
- 10). Sato H, Sato N, Tamaki N, Matsumoto S: Chronic low-perfusion state in children with moyamoya disease following revascularization. Childs Nerv Syst 6: 166– 171, 1990 [DOI] [PubMed] [Google Scholar]
- 11). Araki Y, Takagi Y, Ueda K, Ubukata S, Ishida J, Funaki T, Kikuchi T, Takahashi JC, Murai T, Miyamoto S: Cognitive function of patients with adult moyamoya disease. J Stroke Cerebrovasc Dis 23: 1789– 1794, 2014 [DOI] [PubMed] [Google Scholar]
- 12). Karzmark P, Zeifert PD, Bell-Stephens TE, Steinberg GK, Dorfman LJ: Neurocognitive impairment in adults with moyamoya disease without stroke. Neurosurgery 70: 634– 638, 2012 [DOI] [PubMed] [Google Scholar]
- 13). Weinberg DG, Rahme RJ, Aoun SG, Batjer HH, Bendok BR: Moyamoya disease: functional and neurocognitive outcomes in the pediatric and adult populations. Neurosurg Focus 30: E21, 2011 [DOI] [PubMed] [Google Scholar]
- 14). Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases : Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 52: 245– 266, 2012 [DOI] [PubMed] [Google Scholar]
- 15). Iida H, Nakagawara J, Hayashida K, Fukushima K, Watabe H, Koshino K, Zeniya T, Eberl S: Multicenter evaluation of a standardized protocol for rest and acetazolamide cerebral blood flow assessment using a quantitative SPECT reconstruction program and split-dose 123I-iodoamphetamine. J Nucl Med 51: 1624– 1631, 2010 [DOI] [PubMed] [Google Scholar]
- 16). Yoneda H, Shirao S, Koizumi H, Oka F, Ishihara H, Ichiro K, Kitahara T, Iida H, Suzuki M: Reproducibility of cerebral blood flow assessment using a quantitative SPECT reconstruction program and split-dose 123I-iodoamphetamine in institutions with different γ-cameras and collimators. J Cereb Blood Flow Metab 32: 1757– 1764, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17). Mizumura S, Nakagawara J, Takahashi M, Kumita S, Cho K, Nakajo H, Toba M, Kumazaki T: Three-dimensional display in staging hemodynamic brain ischemia for JET study: objective evaluation using SEE analysis and 3D-SSP display. Ann Nucl Med 18: 13– 21, 2004 [DOI] [PubMed] [Google Scholar]
- 18). Imabayashi E, Matsuda H, Tabira T, Arima K, Araki N, Ishii K, Yamashita F, Iwatsubo T, Japanese Alzheimer's Disease Neuroimaging Initiative : Comparison between brain CT and MRI for voxel-based morphometry of Alzheimer's disease. Brain Behav 3: 487– 493, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19). Wechsler D: Wechsler Adult Intelligence Scale, ed 3. San Antonio, The Psychological Corporation, 1997 [Google Scholar]
- 20). Wechsler D: Wechsler Memory Scale-Revised. San Antonio, The Psychological Corporation, 1987 [Google Scholar]
- 21). Dubois B, Slachevsky A, Litvan I, Pillon B: The FAB: a Frontal Assessment Battery at bedside. Neurology 55: 1621– 1626, 2000 [DOI] [PubMed] [Google Scholar]
- 22). Yoon B, Shim YS, Cheong HK, Hong YJ, Lee KS, Park KH, Ahn KJ, Kim DJ, Kim YD, Choi SH, Yang DW: White matter hyperintensities in mild cognitive impairment: clinical impact of location and interaction with lacunes and medial temporal atrophy. J Stroke Cerebrovasc Dis 23: e365– e372, 2014 [DOI] [PubMed] [Google Scholar]
- 23). Reitan RM: The Halstead-Reitan Neuropsychological Test Battery. Tucson, Neuropsychology Press, 1985 [Google Scholar]
- 24). Deckel AW, Hesselbrock V, Bauer L: Relationship between alcohol-related expectancies and anterior brain functioning in young men at risk for developing alcoholism. Alcohol Clin Exp Res 19: 476– 481, 1995 [DOI] [PubMed] [Google Scholar]
- 25). Terada T, Obi T, Yoshizumi M, Murai T, Miyajima H, Mizoguchi K: Frontal lobe-mediated behavioral changes in amyotrophic lateral sclerosis: are they independent of physical disabilities? J Neurol Sci 309: 136– 140, 2011 [DOI] [PubMed] [Google Scholar]
- 26). Takahashi M, Tanaka K, Miyaoka H: Depression and associated factors of informal caregivers versus professional caregivers of demented patients. Psychiatry Clin Neurosci 59: 473– 480, 2005 [DOI] [PubMed] [Google Scholar]
- 27). Yamanishi T, Tachibana H, Oguru M, Matsui K, Toda K, Okuda B, Oka N: Anxiety and depression in patients with Parkinson's disease. Intern Med 52: 539– 545, 2013 [DOI] [PubMed] [Google Scholar]
- 28). Matsuoka Y, Yoneda K, Sadahira C, Katsuura J, Moriue T, Kubota Y: Effects of skin care and makeup under instructions from dermatologists on the quality of life of female patients with acne vulgaris. J Dermatol 33: 745– 752, 2006 [DOI] [PubMed] [Google Scholar]
- 29). Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis G: Wisconsin Card Sorting Test (WCST) Manual, Revised and Expanded. Odessa, FL, Psychological Assessment Resources, 1993 [Google Scholar]
- 30). Kaku Y, Iihara K, Nakajima N, Kataoka H, Fukuda K, Masuoka J, Fukushima K, Iida H, Hashimoto N: Cerebral blood flow and metabolism of hyperperfusion after cerebral revascularization in patients with moyamoya disease. J Cereb Blood Flow Metab 32: 2066– 2075, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]