Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations

John M. Ringman, Joseph O'Neill, Daniel Geschwind, Luis Medina, Liana G. Apostolova, Yaneth Rodriguez, Barbara Schaffer, Arousiak Varpetian, Benjamin Tseng, Freddy Ortiz, Jaime Fitten, Jeffrey L. Cummings, George Bartzokis

Research output: Contribution to journalArticle

Abstract

Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)1767-1776
Number of pages10
JournalBrain
Volume130
Issue number7
DOIs
StatePublished - Jul 2007

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Diffusion Tensor Imaging
Anisotropy
Alzheimer Disease
Flavin-Adenine Dinucleotide
Mutation
Dementia
Perforant Pathway
White Matter
Asymptomatic Diseases
Frontal Lobe
Linear Models
Biomarkers
Logistic Models
Regression Analysis

Keywords

  • Amyloid precursor protein
  • Biomarker
  • Diffusion tensor imaging
  • Familial Alzheimer's disease
  • Fornix
  • Fractional anisotropy
  • Presenilin-1
  • Presymptomatic
  • White matter

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Ringman, J. M., O'Neill, J., Geschwind, D., Medina, L., Apostolova, L. G., Rodriguez, Y., ... Bartzokis, G. (2007). Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations. Brain, 130(7), 1767-1776. https://doi.org/10.1093/brain/awm102

Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations. / Ringman, John M.; O'Neill, Joseph; Geschwind, Daniel; Medina, Luis; Apostolova, Liana G.; Rodriguez, Yaneth; Schaffer, Barbara; Varpetian, Arousiak; Tseng, Benjamin; Ortiz, Freddy; Fitten, Jaime; Cummings, Jeffrey L.; Bartzokis, George.

In: Brain, Vol. 130, No. 7, 07.2007, p. 1767-1776.

Research output: Contribution to journalArticle

Ringman, JM, O'Neill, J, Geschwind, D, Medina, L, Apostolova, LG, Rodriguez, Y, Schaffer, B, Varpetian, A, Tseng, B, Ortiz, F, Fitten, J, Cummings, JL & Bartzokis, G 2007, 'Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations', Brain, vol. 130, no. 7, pp. 1767-1776. https://doi.org/10.1093/brain/awm102
Ringman, John M. ; O'Neill, Joseph ; Geschwind, Daniel ; Medina, Luis ; Apostolova, Liana G. ; Rodriguez, Yaneth ; Schaffer, Barbara ; Varpetian, Arousiak ; Tseng, Benjamin ; Ortiz, Freddy ; Fitten, Jaime ; Cummings, Jeffrey L. ; Bartzokis, George. / Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations. In: Brain. 2007 ; Vol. 130, No. 7. pp. 1767-1776.
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AU - O'Neill, Joseph

AU - Geschwind, Daniel

AU - Medina, Luis

AU - Apostolova, Liana G.

AU - Rodriguez, Yaneth

AU - Schaffer, Barbara

AU - Varpetian, Arousiak

AU - Tseng, Benjamin

AU - Ortiz, Freddy

AU - Fitten, Jaime

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N2 - Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.

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KW - Familial Alzheimer's disease

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KW - Presenilin-1

KW - Presymptomatic

KW - White matter

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