title: Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer's disease.
abstract: Amyloid imaging studies of presymptomatic familial Alzheimer's disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer's disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical grey matter regions of interest, with increased fractional anisotropy in bilateral putamen. We propose that axonal injury may be an early event in presymptomatic Alzheimer's disease, causing an initial fall in axial and mean diffusivity, which then increases with loss of axonal density. The selective degeneration of long-coursing white matter tracts, with relative preservation of short interneurons, may account for the increase in fractional anisotropy that is seen in the thalamus and caudate presymptomatically. It may be owing to their dense connectivity that imaging changes are seen first in the thalamus and striatum, which then progress to involve other regions in a vulnerable neuronal network.
authors.affiliation: Dementia Research Centre, Box 16 National Hospital for Neurology and Neurosugery, Queen Square, London WC1N 3BG, UK. natalie.ryan@ucl.ac.uk
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Ryan
authors.forename: Shiva
authors.initials: S
authors.lastname: Keihaninejad
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shakespeare
authors.forename: Manja
authors.initials: M
authors.lastname: Lehmann
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Crutch
authors.forename: Ian B
authors.initials: IB
authors.lastname: Malone
authors.forename: John S
authors.initials: JS
authors.lastname: Thornton
authors.forename: Laura
authors.initials: L
authors.lastname: Mancini
authors.forename: Harpreet
authors.initials: H
authors.lastname: Hyare
authors.forename: Tarek
authors.initials: T
authors.lastname: Yousry
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Ridgway
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Marc
authors.initials: M
authors.lastname: Modat
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Alexander
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ourselin
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D058070:Asymptomatic Diseases / Q000453:epidemiology*; D002421:Caudate Nucleus / Q000473:pathology*; D015331:Cohort Studies; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D013788:Thalamus / Q000473:pathology*
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