Genetic influences on atrophy patterns in familial Alzheimer's disease

a comparison of APP and PSEN1 mutations

Rachael I Scahill, Gerard R Ridgway, Jonathan W Bartlett, Josephine Barnes, Natalie S Ryan, Simon Mead, Jonathan Beck, Matthew J Clarkson, Sebastian J Crutch, Jonathan M Schott, Sebastien Ourselin, Jason D Warren, John Hardy, Martin N Rossor, Nick C Fox

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.

Original languageEnglish
Pages (from-to)199-212
Number of pages14
JournalJournal of Alzheimer's Disease
Volume35
Issue number1
DOIs
Publication statusPublished - 29 Mar 2013

Keywords

  • Adult
  • Alzheimer Disease/genetics
  • Amyloid beta-Protein Precursor/genetics
  • Atrophy
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation/genetics
  • Neocortex/pathology
  • Presenilin-1/genetics
  • Temporal Lobe/pathology

Cite this

Genetic influences on atrophy patterns in familial Alzheimer's disease : a comparison of APP and PSEN1 mutations. / Scahill, Rachael I; Ridgway, Gerard R; Bartlett, Jonathan W; Barnes, Josephine; Ryan, Natalie S; Mead, Simon; Beck, Jonathan; Clarkson, Matthew J; Crutch, Sebastian J; Schott, Jonathan M; Ourselin, Sebastien; Warren, Jason D; Hardy, John; Rossor, Martin N; Fox, Nick C.

In: Journal of Alzheimer's Disease, Vol. 35, No. 1, 29.03.2013, p. 199-212.

Research output: Contribution to journalArticle

Scahill, RI, Ridgway, GR, Bartlett, JW, Barnes, J, Ryan, NS, Mead, S, Beck, J, Clarkson, MJ, Crutch, SJ, Schott, JM, Ourselin, S, Warren, JD, Hardy, J, Rossor, MN & Fox, NC 2013, 'Genetic influences on atrophy patterns in familial Alzheimer's disease: a comparison of APP and PSEN1 mutations', Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 199-212. https://doi.org/10.3233/JAD-121255
Scahill, Rachael I ; Ridgway, Gerard R ; Bartlett, Jonathan W ; Barnes, Josephine ; Ryan, Natalie S ; Mead, Simon ; Beck, Jonathan ; Clarkson, Matthew J ; Crutch, Sebastian J ; Schott, Jonathan M ; Ourselin, Sebastien ; Warren, Jason D ; Hardy, John ; Rossor, Martin N ; Fox, Nick C. / Genetic influences on atrophy patterns in familial Alzheimer's disease : a comparison of APP and PSEN1 mutations. In: Journal of Alzheimer's Disease. 2013 ; Vol. 35, No. 1. pp. 199-212.
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abstract = "Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.",
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AU - Barnes, Josephine

AU - Ryan, Natalie S

AU - Mead, Simon

AU - Beck, Jonathan

AU - Clarkson, Matthew J

AU - Crutch, Sebastian J

AU - Schott, Jonathan M

AU - Ourselin, Sebastien

AU - Warren, Jason D

AU - Hardy, John

AU - Rossor, Martin N

AU - Fox, Nick C

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N2 - Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.

AB - Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.

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KW - Amyloid beta-Protein Precursor/genetics

KW - Atrophy

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation/genetics

KW - Neocortex/pathology

KW - Presenilin-1/genetics

KW - Temporal Lobe/pathology

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M3 - Article

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SP - 199

EP - 212

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

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ER -