A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume

Abstract

Atlas normalization, as commonly used by functional data analysis, provides an automated solution to the widely encountered problem of correcting for head size variation in regional and whole-brain morphometric analyses, so long as an age- and population-appropriate target atlas is used. In the present article, we develop and validate an atlas normalization procedure for head size correction using manual total intracranial volume (TIV) measurement as a reference. The target image used for atlas transformation consisted of a merged young and old-adult template specifically created for cross age-span normalization. Automated atlas transformation generated the Atlas Scaling Factor (ASF) defined as the volume-scaling factor required to match each individual to the atlas target. Because atlas normalization equates head size, the ASF should be proportional to TIV. A validation analysis was performed on 147 subjects to evaluate ASF as a proxy for manual TIV measurement. In addition, 19 subjects were imaged on multiple days to assess test–retest reliability. Results indicated that the ASF was (1) equivalent to manual TIV normalization (r = 0.93), (2) reliable across multiple imaging sessions (r = 1.00; mean absolute percentage of difference = 0.51%), (3) able to connect between-gender head size differences, and (4) minimally biased in demented older adults with marked atrophy. Hippocampal volume differences between nondemented (n = 49) and demented (n = 50) older adults (measured manually) were equivalent whether corrected using manual TIV or automated ASF (effect sizes of 1.29 and 1.46, respectively). To provide normative values, ASF was used to automatically derive estimated TIV (eTIV) in 335 subjects aged 15–96 including both clinically characterized nondemented (n = 77) and demented (n = 90) older adults. Differences in eTIV between nondemented and demented groups were negligible, thus failing to support the hypothesis that large premorbid brain size moderates Alzheimer's disease. Gender was the only robust factor that influenced eTIV. Men showed an approximately ∼12% larger eTIV than women. These results demonstrate that atlas normalization using appropriate template images provides a robust, automated method for head size correction that is equivalent to manual TIV correction in studies of aging and dementia. Thus, atlas normalization provides a common framework for both morphometric and functional data analysis.

Introduction

Morphometric analysis of brain structure confronts the challenge that head size markedly differs among individuals—a challenge also present in functional data analysis. Measurement of regional volumes, rates of atrophy, and estimated premorbid whole-brain volume require some form of procedure to measure and account for head size variation. Quantities that have been used for this purpose in morphometric analysis include height Bartzokis et al., 2001, Raz et al., 1997, head circumference Graves et al., 1996, Schofield et al., 1997, and MRI-based measurement of the total intracranial volume (TIV; also sometimes called TICV and ICV) Blatter et al., 1995, Edland et al., 2002, Jenkins et al., 2000, Mathalon et al., 1993. The usual assumption, supported by postmortem findings Davis and Wright, 1977, Epstein and Epstein, 1978, is that these measures serve as proxy variables for the premorbid (unatrophied) brain volume. Normalization by head size increases the robustness of expected mophometric effects, for example, gray-matter volume differences in aging (Mathalon et al., 1993). Moreover, as clinical practice moves to routine use of morphometric variables, automated head size measurement and correction will be required to compare individual patients against normative values.

Here we present a fast, automated procedure for head size correction that is validated against manual TIV measurement. The method uses the volume-scaling factor derived by registration of each individual to an atlas template to automatically generate a good estimate of TIV. Atlas normalization, of this form, is also commonly used in functional data analysis. By using atlas-based head size normalization, the same validated procedures derive robust morphometric quantities for structural comparisons as well as normalized images for between-subject and between-group functional data analysis.