日本  脑影像学中心  松田博史 Hiroshi Matsuda

The Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) was a multicenter study assessing neuroimaging in diagnosis and longitudinal monitoring that was started in 2008 in Japan. All of the participants were recruited at 38 Japanese clinical sites. They were followed up for 2–3 years using 1.5-T MRI, positron emission tomography (PET) using FDG or/and amyloid tracer, biological fluid analysis, and neuropsychological batteries. All of the protocols were designed to be as compatible as possible to those of the ADNI in North America. Participants were 60 to 84 years of age, generally healthy, spoke Japanese, lived at home, and had a study partner. Inclusion and exclusion criteria in J-ADNI are identical to those of ADNI. Briefly, the subjects with mild cognitive impairment (MCI) or AD both had memory complaints, whereas cognitively normal (CN) had none. On Mini–Mental State Examination (MMSE), the range for CN and MCI was 24–30 and for AD, 20–26. The Clinical Dementia Rating (CDR) global score for CN was 0, MCI was 0.5 (memory domain 0.5 mandatory), and the rating for AD was 0.5 or 1. Delayed recall of the Logical Memory IIA subscale of the Wechsler Memory Scale-Revised was used for a memory criterion with cutoff scores based on education: For CN subjects, >9 for 16 years of education, >5 for 10–15 years, and >3 for 0–9 years. For subjects with MCI or AD, Logical Memory IIA scores were <8 for 16 years of education, <4 for 10–15 years, and <2 for 0–9 years. The subjects with MCI had to be largely intact with regard to general cognition and functional performance and could not meet diagnostic criteria for a dementia diagnosis, thus they were classified as single- or multi-domain amnestic MCI. The subjects with mild AD had to satisfy the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for probable AD. Psychoactive drugs were prohibited or restricted as defined in the protocol, and exceptions were approved and recorded. The participant should have Hachinski Ischemic Score of <4, and should not be depressed (Geriatric Depression Scale score <6). Of 715 people assessed for eligibility, 537 met criteria and were enrolled.

The 537 participants underwent brain MRI at baseline. Follow-up MRI was performed at 6, 12, and 24 months for all participants and at 36 months only for late mild cognitive impairment (MCI) and cognitively normal (CN) participants. MCI participants additionally underwent MRI at 18 months. Clinical and cognitive assessments were also performed for all participants at the time of the baseline and follow-up scans. These assessments included MMSE, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS Cog),and CDR-sum of box (CDR-SB). Data were used for analysis from 149 AD, 234 MCI, and 154 CN participants. Amyloid biomarker was examined in 278 participants (83 AD, 112 MCI, 83 CN) and positive amyloid marker was observed in 167 participants (73 AD, 75 MCI, 19 CN). Amyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in MCI and mild AD between J-ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid-positive MCI in J-ADNI and ADNI were remarkably similar, whereas those in mild AD were milder in J-ADNI compared with ADNI.

Little is known about the sample sizes required for clinical trials of AD modifying treatments using atrophy measures from serial brain MRI in the Japanese population.We estimated how large a sample size would be needed for future clinical trials for AD-modifying treatments in Japan using atrophy measures of the brain as a surrogate biomarker. Sample sizes were estimated from the rates of change of the whole brain and hippocampus by the k-means normalized boundary shift integral and cognitive measures (CDR-SB, ADAS-Cog, and MMSE) using the data of 537 J-ADNI participants with a linear mixed-effects model. We also examined the potential use of ApoE status as a trial enrichment strategy. We considered two-arm and equal allocation trials for a hypothetical AD-modifying treatment versus placebo with the scores and above measures as the longitudinal outcomes and with two durations, 1 year and 2 years. In this setting, we calculated sample sizes to detect a 25% reduction in the mean rate of change (annual change) in the outcomes during the trial period with 80% power and a two-sided significance level of 5% with and without comparison to normal aging. The hippocampal atrophy rate required much smaller sample sizes than cognitive measures of AD and MCI. Inclusion of ApoE status reduced sample sizes for AD and MCI patients in the atrophy measures. These results show the potential use of longitudinal hippocampal atrophy measurement using automated image analysis as a progression biomarker and ApoE status as a trial enrichment strategy in a clinical trial of AD-modifying treatment in Japanese people.