title: Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease.
abstract: Alzheimer's disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel-based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, "visual variant," n=93), logopenic variant primary progressive aphasia (lvPPA, "language variant," n=74), and memory-predominant AD categorized as early age-of-onset (EOAD, <65 years, n=114) and late age-of-onset (LOAD, >65 years, n=114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n=80). Even at the earliest clinical stage (CDR=0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant-specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome-specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex-hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome-specific vulnerable networks at the earliest clinical stages of AD.
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.|Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California.|Department of Neurology & Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: Ossenkoppele
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.
authors.forename: Brendan I
authors.initials: BI
authors.lastname: Cohn-Sheehy
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California.
authors.forename: Renaud
authors.initials: R
authors.lastname: La Joie
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Vogel
authors.affiliation: Department of Neurology & Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Christiane
authors.initials: C
authors.lastname: Möller
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.|Dementia Research Centre, UCL Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Manja
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California.
authors.forename: Bart N M
authors.initials: BN
authors.lastname: van Berckel
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Department of Neurology & Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yolande A
authors.initials: YA
authors.lastname: Pijnenburg
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Gorno-Tempini
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: Department of Neurology & Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neurology & Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, California.|Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000145:classification / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D018888:Aphasia, Primary Progressive / Q000473:pathology* / Q000503:physiopathology; D001284:Atrophy / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology* / Q000503:physiopathology; D010641:Phenotype; D013577:Syndrome
keywords: Alzheimer's disease; atrophy; default mode network; early-onset dementia; language; logopenic variant primary progressive aphasia; magnetic resonance imaging (MRI); memory; posterior cortical atrophy; vision; voxel-based morphometry