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Astrocytosis measured by 11C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients

  • IL Han Choo
  • Stephen F. Carter
  • Michael L. Schöll
  • Agneta Nordberg
Original Article

Abstract

Purpose

The Alzheimer’s disease (AD) pathology is characterized by fibrillar amyloid deposits and neurofibrillary tangles, as well as the activation of astrocytosis, microglia activation, atrophy, dysfunctional synapse, and cognitive impairments. The aim of this study was to test the hypothesis that astrocytosis is correlated with reduced gray matter density in prodromal AD.

Methods

Twenty patients with AD or mild cognitive impairment (MCI) underwent multi-tracer positron emission tomography (PET) studies with 11C-Pittsburgh compound B (11C-PIB), 18 F-Fluorodeoxyglucose (18 F-FDG), and 11C-deuterium-L-deprenyl (11C-DED) PET imaging, as well as magnetic resonance imaging (MRI) scanning, cerebrospinal fluid (CSF) biomarker analysis, and neuropsychological assessments. The parahippocampus was selected as a region of interest, and each value was calculated for four different imaging modalities. Correlation analysis was applied between DED slope values and gray matter (GM) densities by MRI. To further explore possible relationships, correlation analyses were performed between the different variables, including the CSF biomarker.

Results

A significant negative correlation was obtained between DED slope values and GM density in the parahippocampus in PIB-positive (PIB + ve) MCI patients (p = 0.025) (prodromal AD). Furthermore, in exploratory analyses, a positive correlation was observed between PIB-PET retention and DED binding in AD patients (p = 0.014), and a negative correlation was observed between PIB retention and CSF Aβ42 levels in MCI patients (p = 0.021), while the GM density and CSF total tau levels were negatively correlated in both PIB + ve MCI (p = 0.002) and MCI patients (p = 0.001). No significant correlation was observed with FDG-PET and with any of the other PET, MRI, or CSF biomarkers.

Conclusions

High astrocytosis levels in the parahippocampus of PIB + ve MCI (prodromal AD) patients suggest an early preclinical influence on cellular tissue loss. The lack of correlation between astrocytosis and CSF tau levels, and a positive correlation between astrocytosis and fibrillar amyloid deposition in clinical demented AD together indicate that parahippocampal astrocytosis might have some causality within the amyloid pathology.

Keywords

Mild cognitive impairment Astrocytosis Amyloid deposition Gray matter density Parahippocampus Multi-tracer PET imaging Alzheimer’s disease 

Notes

Acknowledgments

The present article was funded by the following grants: the Swedish Research Council (project 05817), the Strategic Research Program in Neuroscience at Karolinska Institutet, the Swedish Brain Power, the Old Servants foundation, the Gun and Bertil Stohne’s foundation, the Alzheimer Foundation in Sweden, the Brain Foundation, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, INMIND (grant agreement number 278850, resources) of the European Union’s Seventh Framework Programme for Research and Technological Development (FP7/2007-2013), and the research fund from Chosun University (K206556001-1).

Disclosure statement

None of the authors have any actual or potential conflicts of interest.

Supplementary material

259_2014_2859_Fig2_ESM.gif (17 kb)
Supplementary Figure 1

Correlation analysis between mean gray matter and 11C-DED slope values in the parahippocampus (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups and 11-PIB retention ratio and 11C-DED slope value (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 17 kb)

259_2014_2859_Fig3_ESM.gif (18 kb)
Supplementary Figure 1

Correlation analysis between mean gray matter and 11C-DED slope values in the parahippocampus (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups and 11-PIB retention ratio and 11C-DED slope value (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 17 kb)

259_2014_2859_Fig4_ESM.gif (18 kb)
Supplementary Figure 1

Correlation analysis between mean gray matter and 11C-DED slope values in the parahippocampus (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups and 11-PIB retention ratio and 11C-DED slope value (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 17 kb)

259_2014_2859_Fig5_ESM.gif (17 kb)
Supplementary Figure 1

Correlation analysis between mean gray matter and 11C-DED slope values in the parahippocampus (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups and 11-PIB retention ratio and 11C-DED slope value (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 17 kb)

259_2014_2859_MOESM1_ESM.tif (7.8 mb)
High resolution image (TIFF 7944 kb)
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Supplementary Figure 2

Correlation analyses between CSF total tau values and mean parahippocampal gray matter density (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups, between CSF Aβ1-42 values and parahippocampal 11C-PIB retention ratio (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 16 kb)

259_2014_2859_Fig7_ESM.gif (18 kb)
Supplementary Figure 2

Correlation analyses between CSF total tau values and mean parahippocampal gray matter density (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups, between CSF Aβ1-42 values and parahippocampal 11C-PIB retention ratio (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 16 kb)

259_2014_2859_Fig8_ESM.gif (25 kb)
Supplementary Figure 2

Correlation analyses between CSF total tau values and mean parahippocampal gray matter density (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups, between CSF Aβ1-42 values and parahippocampal 11C-PIB retention ratio (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 16 kb)

259_2014_2859_Fig9_ESM.gif (27 kb)
Supplementary Figure 2

Correlation analyses between CSF total tau values and mean parahippocampal gray matter density (A) for MCI and AD patients, (B) for MCI patients, including PIB positive (PIB + ve) and PIB negative (PIB-ve) groups, between CSF Aβ1-42 values and parahippocampal 11C-PIB retention ratio (C) for MCI and AD patients, (D) for MCI patients. * indicates p < 0.05 by correlation analyses. (GIF 16 kb)

259_2014_2859_MOESM5_ESM.tif (7.9 mb)
High resolution image (TIFF 8127 kb)
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259_2014_2859_MOESM8_ESM.tif (7.4 mb)
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259_2014_2859_MOESM9_ESM.pdf (27 kb)
Supplementary Table 1 (PDF 26 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • IL Han Choo
    • 1
    • 2
  • Stephen F. Carter
    • 1
    • 3
  • Michael L. Schöll
    • 1
    • 6
  • Agneta Nordberg
    • 1
    • 4
    • 5
  1. 1.Department NVS, Center for Alzheimer Research, Translational Alzheimer NeurobiologyKarolinska InstitutetStockholmSweden
  2. 2.Department of Neuropsychiatry, School of MedicineChosun UniversityGwangjuRepublic of Korea
  3. 3.Wolfson Imaging CenterManchester UniversityManchesterUK
  4. 4.Department of Geriatric MedicineKarolinska University Hospital HuddingeStockholmSweden
  5. 5.Department NVS, Center for Alzheimer Research, Translational Alzheimer NeurobiologyKarolinska InstitutetHuddingeSweden
  6. 6.Med Tech West, Department of Neuroscience and RehabilitationGothenburg UniversityGothenburgSweden

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