title: White matter hyperintensities and imaging patterns of brain ageing in the general population.
abstract: White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer's disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer's disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer's disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE-AD variance. Multivariable regression showed significant relationship between white matter hyperintensities volume and hypertension (P = 0.001), diabetes mellitus (P = 0.023), smoking (P = 0.002) and education level (P = 0.003). The only significant association with cognitive tests was with the immediate recall of the California verbal and learning memory test. No significant association was present with the APOE genotype. These results support the hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population. White matter hyperintensities also contribute to brain atrophy patterns in regions related to Alzheimer's disease dementia, in agreement with their known additive role to the likelihood of dementia. Preventive strategies reducing the odds to develop cardiovascular disease and white matter hyperintensities could decrease the incidence or delay the onset of dementia.
authors.affiliation: Institute for Community Medicine, University of Greifswald, Germany Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, USA Department of Psychiatry, University of Greifswald, Germany habesm@uphs.upenn.edu.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Habes
authors.affiliation: Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, USA.
authors.forename: Guray
authors.initials: G
authors.lastname: Erus
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, USA.
authors.forename: Tianhao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Bryan
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, USA.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Department of Data Analysis, Ghent University, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Rosseel
authors.affiliation: Department of Psychiatry, University of Greifswald, Germany.
authors.forename: Deborah
authors.initials: D
authors.lastname: Janowitz
authors.affiliation: Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, USA.
authors.forename: Jimit
authors.initials: J
authors.lastname: Doshi
authors.affiliation: Department of Psychiatry, University of Greifswald, Germany German Centre for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Van der Auwera
authors.affiliation: Department of Neurology, University of Greifswald, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: von Sarnowski
authors.affiliation: Department of Radiology, University of Greifswald, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hegenscheid
authors.affiliation: Department of Radiology, University of Greifswald, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hosten
authors.affiliation: Institute for Genetics and Functional Genomics, University of Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Institute for Community Medicine, University of Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Department of Neurology, University of Greifswald, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schminke
authors.affiliation: Institute for Community Medicine, University of Greifswald, Germany German Centre for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hoffmann
authors.affiliation: Department of Psychiatry, University of Greifswald, Germany German Centre for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Davatzikos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000175:diagnosis / Q000453:epidemiology; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000175:diagnosis / Q000453:epidemiology; D015331:Cohort Studies; D003704:Dementia / Q000175:diagnosis / Q000453:epidemiology; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000639:trends; D008297:Male; D008875:Middle Aged; D011044:Poland / Q000453:epidemiology; D011159:Population Surveillance / Q000379:methods; D012307:Risk Factors; D066127:White Matter / Q000473:pathology*; D055815:Young Adult
keywords: Alzheimer’s disease; brain ageing; cardiovascular disease; mild cognitive impairment; white matter hyperintensities