Impaired default network functional connectivity in autosomal dominant Alzheimer disease

Jasmeer P. Chhatwal, Aaron P. Schultz, Keith Johnson, Tammie L S Benzinger, Clifford Jack, Beau M. Ances, Caroline A. Sullivan, Stephen P. Salloway, John M. Ringman, Robert A. Koeppe, Daniel S. Marcus, Paul Thompson, Andrew Saykin, Stephen Correia, Peter R. Schofield, Christopher C. Rowe, Nick C. Fox, Adam M. Brickman, Richard Mayeux, Eric McDadeRandall Bateman, Anne M. Fagan, Allison M. Goate, Chengjie Xiong, Virginia D. Buckles, John C. Morris, Reisa A. Sperling

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Abstract

Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin- 2 (PSEN2), and amyloid precursor protein (APP)mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p , 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p 5 0.014) and right parietal cortex (p 5 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)736-744
Number of pages9
JournalNeurology
Volume81
Issue number8
DOIs
StatePublished - Aug 20 2013
Externally publishedYes

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Alzheimer Disease
Magnetic Resonance Imaging
Parietal Lobe
Mutation
Gyrus Cinguli
Dementia
Presenilin-2
Presenilin-1
Connectivity
Alzheimer's Disease
Amyloid beta-Protein Precursor
Multicenter Studies
Carrier
Biomarkers
Clinical Trials
Onset
Rating
Parietal Cortex

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Chhatwal, J. P., Schultz, A. P., Johnson, K., Benzinger, T. L. S., Jack, C., Ances, B. M., ... Sperling, R. A. (2013). Impaired default network functional connectivity in autosomal dominant Alzheimer disease. Neurology, 81(8), 736-744. https://doi.org/10.1212/WNL.0b013e3182a1aafe

Impaired default network functional connectivity in autosomal dominant Alzheimer disease. / Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Benzinger, Tammie L S; Jack, Clifford; Ances, Beau M.; Sullivan, Caroline A.; Salloway, Stephen P.; Ringman, John M.; Koeppe, Robert A.; Marcus, Daniel S.; Thompson, Paul; Saykin, Andrew; Correia, Stephen; Schofield, Peter R.; Rowe, Christopher C.; Fox, Nick C.; Brickman, Adam M.; Mayeux, Richard; McDade, Eric; Bateman, Randall; Fagan, Anne M.; Goate, Allison M.; Xiong, Chengjie; Buckles, Virginia D.; Morris, John C.; Sperling, Reisa A.

In: Neurology, Vol. 81, No. 8, 20.08.2013, p. 736-744.

Research output: Contribution to journalArticle

Chhatwal, JP, Schultz, AP, Johnson, K, Benzinger, TLS, Jack, C, Ances, BM, Sullivan, CA, Salloway, SP, Ringman, JM, Koeppe, RA, Marcus, DS, Thompson, P, Saykin, A, Correia, S, Schofield, PR, Rowe, CC, Fox, NC, Brickman, AM, Mayeux, R, McDade, E, Bateman, R, Fagan, AM, Goate, AM, Xiong, C, Buckles, VD, Morris, JC & Sperling, RA 2013, 'Impaired default network functional connectivity in autosomal dominant Alzheimer disease', Neurology, vol. 81, no. 8, pp. 736-744. https://doi.org/10.1212/WNL.0b013e3182a1aafe
Chhatwal JP, Schultz AP, Johnson K, Benzinger TLS, Jack C, Ances BM et al. Impaired default network functional connectivity in autosomal dominant Alzheimer disease. Neurology. 2013 Aug 20;81(8):736-744. https://doi.org/10.1212/WNL.0b013e3182a1aafe
Chhatwal, Jasmeer P. ; Schultz, Aaron P. ; Johnson, Keith ; Benzinger, Tammie L S ; Jack, Clifford ; Ances, Beau M. ; Sullivan, Caroline A. ; Salloway, Stephen P. ; Ringman, John M. ; Koeppe, Robert A. ; Marcus, Daniel S. ; Thompson, Paul ; Saykin, Andrew ; Correia, Stephen ; Schofield, Peter R. ; Rowe, Christopher C. ; Fox, Nick C. ; Brickman, Adam M. ; Mayeux, Richard ; McDade, Eric ; Bateman, Randall ; Fagan, Anne M. ; Goate, Allison M. ; Xiong, Chengjie ; Buckles, Virginia D. ; Morris, John C. ; Sperling, Reisa A. / Impaired default network functional connectivity in autosomal dominant Alzheimer disease. In: Neurology. 2013 ; Vol. 81, No. 8. pp. 736-744.
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abstract = "Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin- 2 (PSEN2), and amyloid precursor protein (APP)mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p , 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p 5 0.014) and right parietal cortex (p 5 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.",
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T1 - Impaired default network functional connectivity in autosomal dominant Alzheimer disease

AU - Chhatwal, Jasmeer P.

AU - Schultz, Aaron P.

AU - Johnson, Keith

AU - Benzinger, Tammie L S

AU - Jack, Clifford

AU - Ances, Beau M.

AU - Sullivan, Caroline A.

AU - Salloway, Stephen P.

AU - Ringman, John M.

AU - Koeppe, Robert A.

AU - Marcus, Daniel S.

AU - Thompson, Paul

AU - Saykin, Andrew

AU - Correia, Stephen

AU - Schofield, Peter R.

AU - Rowe, Christopher C.

AU - Fox, Nick C.

AU - Brickman, Adam M.

AU - Mayeux, Richard

AU - McDade, Eric

AU - Bateman, Randall

AU - Fagan, Anne M.

AU - Goate, Allison M.

AU - Xiong, Chengjie

AU - Buckles, Virginia D.

AU - Morris, John C.

AU - Sperling, Reisa A.

PY - 2013/8/20

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N2 - Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin- 2 (PSEN2), and amyloid precursor protein (APP)mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p , 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p 5 0.014) and right parietal cortex (p 5 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.

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