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Original Contributions |

Prediction of Cognitive Decline by Positron Emission Tomography of Brain Amyloid and Tau

Gary W. Small, MD; Prabha Siddarth, PhD; Vladimir Kepe, PhD; Linda M. Ercoli, PhD; Alison C. Burggren, PhD; Susan Y. Bookheimer, PhD; Karen J. Miller, PhD; Jeanne Kim, PsyD; Helen Lavretsky, MD; S.-C. Huang, PhD; Jorge R. Barrio, PhD
Arch Neurol. 2012;69(2):215-222. doi:10.1001/archneurol.2011.559.
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Objective To determine whether 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) brain regional values in individuals without dementia predict and correlate with future cognitive change.

Design Two-year, longitudinal follow-up study.

Setting A university research institute.

Participants Volunteer sample of 43 middle-aged and older persons (median age, 64 years), including 21 with mild cognitive impairment (MCI) and 22 with normal aging.

Main Outcome Measures Longitudinal [18F]FDDNP positron emission tomography (PET) binding values in the medial and lateral temporal, posterior cingulate, parietal, frontal, and global (mean) regions of interest; neuropsychological test battery measuring 5 cognitive domains, including memory, language, attention (and information-processing speed), executive functioning, and visuospatial ability.

Results For the entire study group (MCI and normal aging), increases in frontal, posterior cingulate, and global binding at follow-up correlated with progression of memory decline (r = −0.32 to −0.37, P = .03 to .01) after 2 years. Moreover, higher baseline [18F]FDDNP binding was associated with future decline in most cognitive domains, including language, attention, executive, and visuospatial abilities (r = −0.31 to −0.56, P = .05 to .002). For the MCI group, frontal and parietal [18F]FDDNP binding yielded the greatest diagnostic accuracy in identifying converters to Alzheimer disease vs nonconverters after 2 years, with an area under the receiver operating characteristic curve of 0.88 (95% CI, 0.72-1.00) compared with 0.68 (95% CI, 0.45-0.91) for medial temporal binding.

Conclusions [18F]FDDNP PET regional binding patterns are consistent with known neuropathologic patterns of plaque and tangle brain accumulation, spreading from the medial temporal to other neocortical regions as disease progresses. Because binding patterns predict future cognitive decline and increase over time along with clinical decline, [18F]FDDNP PET scanning may have practical utility in identifying people at risk for future cognitive decline and in tracking the effectiveness of novel interventions designed to prevent or delay neurodegeneration and cognitive decline.

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Figures

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Figure 1. Representative regions of interest (ROIs). The magnetic resonance images show left and right ROIs (shaded in purple) used for the ROI relative distribution volume analyses, superimposed on the Ch2bet template at the indicated Montreal Neurological Institute coordinates. Images were drawn using MRIcro for Windows (version 1.39, build 4; http://www.cabiatl.com/mricro/).

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Figure 2. Plot of global 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) binding change vs memory change. For the entire study group (N = 43), global [18F]FDDNP binding changes correlated with memory domain score changes at follow-up (t41 = −2.55, r = −0.37, P = .01). CTL indicates control; MCI, mild cognitive impairment.

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Figure 3. Mean cognitive change in study participants with stable vs increased global 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) binding values. Participants who increased in their global [18F]FDDNP binding had greater memory decline at follow-up compared with those who remained stable. Error bars indicate SDs.

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Figure 4. Plot of baseline 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) binding vs executive function change score for mild cognitive impairment (MCI). Gray diamonds indicate MCI patients who remained in the MCI group at follow-up; black diamonds denote MCI patients who converted to Alzheimer disease status at follow-up. The vertical lines indicate zero change (follow-up minus baseline). The horizontal lines indicate the cutoff values for [18F]FDDNP binding chosen based on receiver operating characteristic curves (medial temporal, 1.135; frontal and parietal, 1.07). T1 indicates time 1 (baseline).

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Figure 5. Baseline and follow-up 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) parametric images of a patient with mild cognitive impairment (MCI) who did not convert to Alzheimer disease (AD) after 2 years and a patient who did. A, The parametric [18F]FDDNP scans of the MCI nonconverter showed mild frontal (upper scans) and medial temporal (lower scans) binding at baseline (left) and at follow-up. B, The MCI converter also showed high medial temporal binding at baseline and follow-up but also demonstrated more extensive baseline binding in frontal (upper images) and lateral temporal regions. Warmer colors (yellows, reds) indicate higher binding levels. DVR indicates relative distribution volume.

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