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Cited by 290Dementia and Cognitive Impairment ResearchAdvanced Neuroimaging Techniques and ApplicationsAlzheimer's disease research and treatments

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

Ringman, J. M., O'Neill, J., Geschwind, D., Medina, L., Apostolova, L. G., Rodriguez, Y., Schaffer, B., Varpetian, A. +5 more·2007·Brain
DOI 10.1093/brain/awm102
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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.

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  • A few DTI studies on white matter alterations in autosomal-dominant Alzheimer's disease have been previously conducted.

    “A few DTI studies on white matter alterations in autosomal-dominant Alzheimer’s disease have been previously conducted (Ringman et al., 2007; Ryan et al., 2013; Parra et al., 2015; Sanchez-Valle et al., 2016).”

    From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Ringman et al., 2007

  • Previous DTI studies in autosomal-dominant Alzheimer's disease did not estimate years from symptom onset (EYO), which reduced the sensitivity to detect DTI changes that occur in close proximity to the onset of dementia symptoms.

    “or did not estimate years from symptom onset (EYO) (Ringman et al., 2007; Ryan et al., 2013; Parra et al., 2015), which reduced the sensitivity to detect DTI changes that occur in close proximity to the onset of dementia symptoms.”

    From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Ringman et al., 2007

  • Previous DTI studies in autosomal-dominant Alzheimer's disease lacked sufficient statistical power, considering relatively low sample sizes (n = 8 to 18 asymptomatic carriers), to detect the subtle pre-symptomatic phase.

    “However, these studies either lacked sufficient statistical power considering the relatively low sample sizes (n = 8 to 18 of asymptomatic carriers) to detect subtle pre-symptomatic phase”

    From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Ringman et al., 2007

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Authors
Ringman, J. M., O'Neill, J., Geschwind, D., Medina, L., Apostolova, L. G., Rodriguez, Y., Schaffer, B., Varpetian, A., Tseng, B., Ortiz, F., Fitten, J., Cummings, J. L., & Bartzokis, G.
Affiliations
University of Southern California (US)
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2007-05-29
Volume
130
Issue
7
Pages
1767-1776
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awm102
OpenAlex
W2111425471
Cited by
290
References
37
Citations by year
2026: 1 · 2025: 12 · 2024: 10 · 2023: 9 · 2022: 8 · 2021: 10 · 2020: 11 · 2019: 11 · 2018: 8 · 2017: 10 · 2016: 13 · 2015: 13 · 2014: 14 · 2013: 24 · 2012: 21
FWCI
19.78
Type
journal article
Language
en
Open access
closed
Locations
  • Brain (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (K08 AG-22228, K08AG022228, P50AG016570, AG 16570)
  • National Center for Research Resources ((M01 RR00865), M01RR000865)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
familial Alzheimer's disease, presymptomatic carriers, preclinical Alzheimer's disease, white matter integrity, fractional anisotropy, fornix, perforant path, genetic risk prediction, white matter degeneration, hippocampal volume, disease progression prediction, Clinical Dementia Rating
MeSH terms
Adult, Age Factors, Alzheimer Disease, Brain, Brain Mapping, Female, Heterozygote, Humans, Image Processing, Computer-Assisted, Male, Mutation, Neuropsychological Tests, Psychiatric Status Rating Scales, Anisotropy, Fornix, Brain, Diffusion Magnetic Resonance Imaging

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