title: The effects of intracranial volume adjustment approaches on multiple regional MRI volumes in healthy aging and Alzheimer's disease.
abstract: In neurodegeneration research, normalization of regional volumes by intracranial volume (ICV) is important to estimate the extent of disease-driven atrophy. There is little agreement as to whether raw volumes, volume-to-ICV fractions or regional volumes from which the ICV factor has been regressed out should be used for volumetric brain imaging studies. Using multiple regional cortical and subcortical volumetric measures generated by Freesurfer (51 in total), the main aim of this study was to elucidate the implications of these adjustment approaches. Magnetic resonance imaging (MRI) data were analyzed from two large cohorts, the population-based PIVUS cohort (N = 406, all subjects age 75) and the Alzheimer disease Neuroimaging Initiative (ADNI) cohort (N = 724). Further, we studied whether the chosen ICV normalization approach influenced the relationship between hippocampus and cognition in the three diagnostic groups of the ADNI cohort (Alzheimer's disease, mild cognitive impairment, and healthy individuals). The ability of raw vs. adjusted hippocampal volumes to predict diagnostic status was also assessed. In both cohorts raw volumes correlate positively with ICV, but do not scale directly proportionally with it. The correlation direction is reversed for all volume-to-ICV fractions, except the lateral and third ventricles. Most gray matter fractions are larger in females, while lateral ventricle fractions are greater in males. Residual correction effectively eliminated the correlation between the regional volumes and ICV and removed gender differences. The association between hippocampal volumes and cognition was not altered by ICV normalization. Comparing prediction of diagnostic status using the different approaches, small but significant differences were found. The choice of normalization approach should be carefully considered when designing a volumetric brain imaging study.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Voevodskaya
authors.affiliation: Department of Neuroimaging, Institute of Psychiatry, King's College London London, UK ; NIHR Biomedical Research Centre for Mental Health and NIHR Biomedical Research Unit for Dementia London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.affiliation: Department of Radiology, Uppsala University Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Nordenskjöld
authors.affiliation: Department of Radiology, Uppsala University Uppsala, Sweden.
authors.forename: Joel
authors.initials: J
authors.lastname: Kullberg
authors.affiliation: Department of Radiology, Uppsala University Uppsala, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Ahlström
authors.affiliation: Department of Medical Sciences, Uppsala University Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet Stockholm, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.affiliation: Department of Radiology, Uppsala University Uppsala, Sweden.
authors.forename: Elna-Marie
authors.initials: EM
authors.lastname: Larsson
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet Stockholm, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Westman
keywords: Alzheimer's disease; gender dimorphism; healthy aging; intracranial volume; neuroimaging; normalization