Now we confront a super aging society in Japan. In the situation, it is important to preserve our cognitive function for entire life by preventing us from pathological brain aging. To perform the aim, we have built a large brain magnetic resonance imaging (MRI) database from around 3000 subjects aged from five to 80 in order to reveal how brain develops and ages with not only cross-sectional but longitudinal designs. We have also collected several cognitive functions, lifestyle such as eating and sleeping habits, and genetic data. Using the database, we have revealed normal brain development and aging, and also have revealed what factors affect brain development and aging. In performing these analyses, longitudinal analysis is very important, for we can reduce the influences of inter-individual variability of several factors such as differences of brain shapes. These findings help understanding the mechanism of brain development and aging as well as performing differential diagnosis or diagnosis at an early stage of several diseases/disorders such as autism and Alzheimer's disease.

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The Ishikawa Brain Imaging Study (IBIS) was initiated in 2002 to investigate the role of brain imaging for early and objective assessment of Alzheimer's disease (AD) and other forms of neurodegenerative diseases. Until now, we have studied 1365 volunteer based subjects and 590 patients with dementia using MRI and ¹⁸F-fluorodeoxyglucose PET along with neuropsychological tests and other biomarkers. We have demonstrated an age-related normalcy rate decline in volunteer based population. We also have demonstrated diverse atrophic patterns in a spectrum of AD in that a subset of patients are likely to show posterior cingulate atrophy rather than hippocampal atrophy, which is associated with greater metabolic burden. Because IBIS is a single center study, it would be important to see how such a large collection of data sets can be used in conjunction with multi-center studies such as J-ADNI.

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The last 10 years have seen major changes in multicenter clinical trials involving diagnostic imaging in Alzheimer's disease (AD) and other dementias. The following broad trends can be clearly identified: changes from a) evaluation of a single modality to that of multiple modalities not restricted to images; b) diagnostic imaging to use as biomarkers; c) early diagnosis to very early diagnosis; and d) observational studies to interventional studies. Representative multicenter clinical trials related to dementia include "Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function" (J-COSMIC), "Study on Diagnosis of early Alzheimer's disease-Japan" (SEAD-Japan), and "Alzheimer's disease neuroimaging initiative" (ADNI). Aside from clinical evaluation and neuropsychological tests, evaluations in the J-COSMIC and SEAD-Japan studies were primarily based on cerebral blood flow SPECT and FDG-PET, respectively. Conversely, evaluation in the ADNI study, for the comprehensive diagnostic system, is based on imaging modalities such as MRI, FDG-PET, and amyloid PET, and various types of biomarkers such as genes and cerebrospinal fluid biomarkers. The standardized evaluation techniques regarding AD onset and progression established in these studies are expected to significantly contribute to the development of disease-modifying drugs.

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Voxel-based morphometry (VBM) is widely used in analyzing structural MRI. Recently, several studies employ longitudinal VBM to explore the longitudinal change of grey matter in various disease such as Alzheimer disease or schizophrenia. In performing longitudinal VBM one needs to consider how to preprocess the images and how to build the statistical model. In addition to that, several studies draw attention that different voxel dimension or upgrade of scanner software can result in the different preprocessed images. Longitudinal analysis is inevitable to unveil the mechanism of several diseases, so establishing standard method is needed.

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The ADNI (Alzheimer's Disease Neuroimaging Initiative), the large-scale multi-site clinical study to develop the surrogate markers which lead directly to the essential process of Alzheimer's disease, was launched by 2005 in United States of America. It aims to develop the way to assess the stages of progress of Alzheimer's disease objectively and accurately through a variety of examinations such as clinical, psychological, imaging, biochemical ones. These examinations had been performed for two or three years with 6 month intervals. Especially, the methods to capture the structural changes caused by disease using brain structural MRI have been know as objective and reproducible surrogate biomarker. However, image quality of MRI brain image depends on scanners and imaging protocols, therefore it is necessary to use a consistent imaging protocol and scanner for the longitudinal analysis. Moreover, several pre-processing such as geometrical distortion correction and intensity inhomogeneity correction are needed to improve reliability of structural analysis. ADNI data base have been available for worldwide researchers, it can contribute to development of longitudinal analysis method due to disclosure of the measurement bias in the algorism of longitudinal analysis through a reproducible examinations. It is important to use the algorism considering "symmetric transformation" and "transitivity of measurement for volume of interest".

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