P1‐109: Rates of regional brain atrophy and gain in power for assessment of cognitive decline in clinical trials

Clinical trials of Alzheimer's disease (AD) are increasingly exploiting MRI measures of progressive brain tissue loss to assess if pharmacologic interventions have a disease modifying effect. However, there is an ongoing debate which brain regions provide the highest power. Moreover, the extent to which MRI can boost power in detecting a slowing in cognitive decline, the primary outcome in clinical trials, is not established. This study had two goals: First, to identify the brain regions that provide the highest sensitivity in measuring brain tissue loss and second to determine how much variance in cognitive decline each brain region explains. The study included age-matched groups of 79 patients with mild AD, 223 MCI patients and 135 cognitive normal subjects, who all had 3 consecutive clinical and MRI assessments within a year as part of the ADNI project. Ninety-six brain volumes were automatically segmented using Freesurfer software. Linear mixed effects statistics was used to estimate group rates and maximum likelihood tests were used to determine how much each brain region explains cognitive decline. The volumes of hippocampus, followed by amygdale, lateral ventricles, parahippocampal gyrus and inferior/superior temporal cortex provided the highest sensitivity in measuring brain change. Taken all regions together showed that the entorhinal cortex [Likelihood ratio (LR): 8.6; p = 0.01) explained most of the cognitive decline in AD whereas the middle temporal cortex (LR: 4.7; p = 0.03) and parahippocampal gyrus (LR: 5.7, p = 0.02) explained most cognitive decline in MCI and controls, respectively. Sample size estimations for a hypothetical trial (25% slowing of progression within a year, 90% power, alpha = 0.05) in which the primary outcome measures are either rates of brain atrophy (using MRI), cognitive decline (using ADAS-Cog) or cognitive decline conditioned for rates of brain atrophy are listed in the table. For example, 800 subjects/arm are required if the outcome measure is ADAS-Cog compared to only 98 subjects/arm if the outcome measure is MRI. Atrophy rates of temporal lobe structures and ventricular dilatation are the most sensitive brain alterations in AD, MCI and normal aging and also can increase power of clinical trials.