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Original Investigation |

Cross-sectional and Longitudinal Analysis of the Relationship Between Aβ Deposition, Cortical Thickness, and Memory in Cognitively Unimpaired Individuals and in Alzheimer Disease

Vincent Doré, PhD1,2; Victor L. Villemagne, MD2,3; Pierrick Bourgeat, PhD1; Jurgen Fripp, PhD1; Oscar Acosta, PhD4; Gael Chetélat, PhD5; Luping Zhou, PhD1; Ralph Martins, PhD6; Kathryn A. Ellis, PhD3,8,10; Colin L. Masters, MD3,9; David Ames, MD8,10; Oliver Salvado, PhD1; Christopher C. Rowe, MD2
[+] Author Affiliations
1CSIRO Preventative Health National Research Flagship ICTC, the Australian e-Health Research Centre–BioMedical, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
2Department of Nuclear Medicine and Centre for PET and Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
3The Mental Health Research Institute and University of Melbourne, Parkville, Victoria, Australia
4INSERM and Université de Rennes 1, LTSI, Rennes, France
5INSERM-EPHE–Université de Caen/Basse-Normandie, Unité U923, GIP Cyceron, CHU Côte de Nacre, Caen, France
6Edith Cowan University, School of Exercise, Biomedica, and Health Sciences, Perth, Western Australia, Australia
8National Ageing Research Institute, Parkville, Victoria, Australia
9Centre for Neurosciences and University of Melbourne, Parkville, Victoria, Australia
10Academic Unit for Psychiatry of Old Age, Department of Psychiatry, University of Melbourne, St Vincent’s Aged Psychiatry Service, St George’s Hospital, Melbourne, Victoria, Australia
JAMA Neurol. 2013;70(7):903-911. doi:10.1001/jamaneurol.2013.1062.
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Importance  β-amyloid (Aβ) deposition is one of the hallmarks of Alzheimer disease. Aβ deposition accelerates gray matter atrophy at early stages of the disease even before objective cognitive impairment is manifested. Identification of at-risk individuals at the presymptomatic stage has become a major research interest because it will allow early therapeutic interventions before irreversible synaptic and neuronal loss occur. We aimed to further characterize the cross-sectional and longitudinal relationship between Aβ deposition, gray matter atrophy, and cognitive impairment.

Objective  To investigate the topographical relationship of Aβ deposition, gray matter atrophy, and memory impairment in asymptomatic individuals with Alzheimer disease pathology as assessed by Pittsburgh compound B positron emission tomography (PiB-PET).

Design  Regional analysis was performed on the cortical surface to relate cortical thickness to PiB retention and episodic memory.

Setting  The Australian Imaging, Biomarkers, and Lifestyle Study of Aging, Austin Hospital, Melbourne, Australia.

Participants  Ninety-three healthy elderly control subjects (NCs) and 40 patients with Alzheimer disease from the Australian Imaging, Biomarkers, and Lifestyle Study of Aging cohort.

Intervention  Participants underwent neuropsychological evaluation as well as magnetic resonance imaging and PiB-PET scans. Fifty-four NCs underwent repeated scans and neuropsychological evaluation 18 and 36 months later.

Main Outcomes and Measures  Correlations between cortical thickness, PiB retention, and episodic memory.

Results  There was a significant reduction in cortical thickness in the precuneus and hippocampus associated with episodic memory impairment in the NC PiB-positive (NC+) group when compared with the NC group. Cortical thickness was also correlated negatively with neocortical PiB in the NC+ group. Longitudinal analysis showed a faster rate of gray matter (GM) atrophy in the temporal lobe and the hippocampi of the NC+ group. Over time, GM atrophy became more extensive in the NC+ group, especially in the temporal lobe.

Conclusions and Relevance  In asymptomatic individuals, Aβ deposition is associated with GM atrophy and memory impairment. The earliest signs of GM atrophy were detected in the hippocampus and the posterior cingulate and precuneus regions, and with disease progression, atrophy became more extensive in the temporal lobes. These findings support the notion that Aβ deposition is not a benign process and that interventions with anti-Aβ therapy at these early stages have a higher chance to be effective.

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Figure 1.
Cortical Thickness Between the Healthy Control Pittsburgh Compound B–Negative and Alzheimer Disease Groups

P value is less than.0005 (false discovery rate corrected). P value maps are of a vertex-wise t test. Gray matter atrophy is significantly more prominent and widespread in the Alzheimer disease group than in the healthy control Pittsburgh compound B–negative group. INF indicates inferior; LAT, lateral; LT, left; MED, medial; RT, right; and SUP, superior.

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Figure 2.
Cortical Thickness Estimation of the Healthy Control Pittsburgh Compound B–Negative (NC) and Healthy Control Pittsburgh Compound B–Positive (NC+) Groups

P value is less than.05 (false discovery rate corrected). Groups wereevaluated in the 3 different anatomical regions of interest. P value maps are of the t test between groups. Compared with the NCgroup, significantly greater atrophy was observed in the hippocampus and precuneus and posterior cingulate gyrus of the NC+ group. INF indicates inferior; LAT, lateral; LT, left; MED, medial; RT, right; and SUP, superior.

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Figure 3.
Correlation Between Cortical Thickness and Neocortical Pittsburgh Compound B in the Healthy Control Pittsburgh Compound B–Positive Group

Data are reported in P value maps. P value is less than .05 (false discovery rate corrected). Gray matter atrophy was significantly associated with neocortical standardized uptake value ratio in the healthy control Pittsburgh compound B–positive group bilaterally in the precuneus and posterior cingulate gyrus and in the right temporal lobe and hippocampus. INF indicates inferior; LAT, lateral; LT, left; MED, medial; RT, right; and SUP, superior.

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Figure 4.
Gray Matter Atrophy in the Healthy Control Pittsburgh Compound B–Negative (NC) and Healthy Control Pittsburgh Compound B–Positive (NC+) Groups

Rates are reported in millimeters per year. Gray matter loss over 36 months was more extensive, especially in the temporal, precuneus and posterior cingulate gyrus, and occipital cortices, in the NC+ group compared with the NC group. Faster rates of gray matter loss were observed in the hippocampal regions. INF indicates inferior; LAT, lateral; LT, left; MED, medial; RT, right; and SUP, superior.

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Figure 5.
Significant Differences in the Global Rate of Gray Matter Atrophy Between the Healthy Control Pittsburgh Compound B–Negative (NC) and Healthy Control Pittsburgh Compound B–Positive (NC+) Groups

Data are reported in P value maps. The rates of atrophy in the NC+ group over 36 months were significantly faster than in the NC group in both temporal lobes and the hippocampi. INF indicates inferior; LAT, lateral; LT, left; MED, medial; RT, right; and SUP, superior.

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Figure 6.
Significant Cortical Thickness Loss in the Healthy Control Pittsburgh Compound B–Positive Group at the 18-Month and 36-Month Follow-ups

Panel A indicates 18-month and panel B indicates 36-month follow-ups. Data are reported in P value maps. In the healthy control Pittsburgh compound B–positive group, there was a steady progression of cortical thickness loss. INF indicates inferior; LAT, lateral; LT, left; MED, medial; RT, right; and SUP, superior.

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