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Original Investigation |

Cerebrospinal Fluid Aβ42, Phosphorylated Tau181, and Resting-State Functional Connectivity

Liang Wang, MD1; Matthew R. Brier, BS1; Abraham Z. Snyder, MD, PhD1,2; Jewell B. Thomas, BA1; Anne M. Fagan, PhD1,3,4; Chengjie Xiong, PhD3,5; Tammie L. Benzinger, MD, PhD2,3,4; David M. Holtzman, MD1,3,4; John C. Morris, MD1,3; Beau M. Ances, MD, PhD1,3,4
[+] Author Affiliations
1Department of Neurology, Washington University in St Louis, St Louis, Missouri
2Department of Radiology, Washington University in St Louis, St Louis, Missouri
3The Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Department of Neurology, Washington University in St Louis, St Louis, Missouri
4Hope Center for Neurological Disorders, Department of Neurology, Washington University in St Louis, St Louis, Missouri
5Division of Biostatistics, Washington University in Saint Louis, Saint Louis, Missouri
JAMA Neurol. 2013;70(10):1242-1248. doi:10.1001/jamaneurol.2013.3253.
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Importance  Resting-state functional connectivity magnetic resonance imaging has great potential for characterizing pathophysiological changes during the preclinical phase of Alzheimer disease.

Objective  To assess the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals.

Design, Setting, and Participants  Cross-sectional cohort study at The Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University in St Louis, St Louis, Missouri, among 207 older adults with normal cognition (Clinical Dementia Rating, 0).

Main Outcomes and Measures  Resting-state functional connectivity magnetic resonance imaging measures of default mode network integrity.

Results  Decreased cerebrospinal fluid Aβ42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions. Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas. Similar resting-state functional connectivity magnetic resonance imaging findings in relation to cerebrospinal fluid biomarkers were obtained using region-of-interest analyses and voxelwise correlation mapping.

Conclusions and Relevance  Both Aβ and tau pathology affect default mode network integrity before clinical onset of Alzheimer disease.

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Figure.
Voxelwise Analyses Assessing Functional Connectivity of the Posterior Cingulate Cortex (PCC) in Cognitively Normal Individuals With Abnormal Levels of Cerebrospinal Fluid Aβ42 or Phosphorylated Tau181

Two-sample t test assessed decreases (hot color) or increases (cold color) in functional connectivity of the PCC in cerebrospinal fluid Aβ42–positive individuals (≤500 pg/mL) compared with cerebrospinal fluid Aβ42–negative individuals (>500 pg/mL) (A) and in cerebrospinal fluid phosphorylated tau181–positive individuals (≥80 pg/mL) compared with cerebrospinal fluid phosphorylated tau181–negative individuals (<80 pg/mL) (B). Maps were displayed at a voxel-level t exceeding 2.5 and cluster size exceeding 35 voxels. Circles represent regions reaching a significance level of P < .05 (solid) and P < .10 but P > .05 (dashed), corrected at the cluster level. Detailed information about anatomical location and statistics of observed functional connectivity differences is given in eTable 3 in the Supplement.

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