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.
Similar content being viewed by others
References
Streit WJ, Braak H, Xue QS, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 2009;118:475–85. doi:10.1007/s00401-009-0556-6.
Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ. Astrocytes in Alzheimer’s disease. Neurotherapeutics. 2010;7:399–412. doi:10.1016/j.nurt.2010.05.017.
Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, et al. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience. 1994;62:15–30.
Saura J, Bleuel Z, Ulrich J, Mendelowitsch A, Chen K, Shih JC. Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry. Neuroscience. 1996;70:755–74. doi:10.1016/S0306-4522(96)83013-2.
Fowler JS, Logan J, Volkow ND, Wang GJ. Translational neuroimaging: positron emission tomography studies of monoamine oxidase. Mol Imaging Biol. 2005;7:377–87. doi:10.1007/s11307-005-0016-1.
Fowler JS, MacGregor RR, Wolf AP, Arnett CD, Dewey SL, Schlyer D, et al. Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science. 1987;235:481–5.
Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med. 2012;53:37–46. doi:10.2967/jnumed.110.087031.
Hirvonen J, Kailajarvi M, Haltia T, Koskimies S, Nagren K, Virsu P. Assessment of MAO-B occupancy in the brain with PET and [11C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther. 2009;85:506–12. doi:10.1038/clpt.2008.241.
Santillo AF, Gambini JP, Lannfelt L, Langstrom B, Ulla-Marja L, Kilander L, et al. In vivo imaging of astrocytosis in Alzheimer’s disease: an (1) (1) C-L-deuteriodeprenyl and PIB PET study. Eur J Nucl Med Mol Imaging. 2011;38:2202–8. doi:10.1007/s00259-011-1895-9.
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280–92. doi:10.1016/j.jalz.2011.03.003.
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9:1118–27. doi:10.1016/S1474-4422(10)70223-4.
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–29. doi:10.1016/S1474-4422(14)70090-0.
Bourgeat P, Chetelat G, Villemagne VL, Fripp J, Raniga P, Pike K, et al. Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology. 2010;74:121–7. doi:74/2/121 [pii] 10.1212/WNL.0b013e3181c918b5.
Chetelat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, et al. Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol. 2010;67:317–24. doi:10.1002/ana.21955.
Cohen AD, Price JC, Weissfeld LA, James J, Rosario BL, Bi W. Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve. J Neurosci. 2009;29:14770–8. doi:10.1523/JNEUROSCI.3669-09.2009.
Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF. Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C] PIB and [18F] FDG PET study. Neurology. 2007;68:501–8. doi:10.1212/01.wnl.0000244749.20056.d4.
Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I. Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain. 2006;129:2856–66. doi:10.1093/brain/awl178.
Fagan AM, Head D, Shah AR, Marcus D, Mintun M, Morris JC, et al. Decreased cerebrospinal fluid Abeta (42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol. 2009;65:176–83. doi:10.1002/ana.21559.
Forsberg A, Almkvist O, Engler H, Wall A, Langstrom B, Nordberg A. High PIB retention in Alzheimer’s disease is an early event with complex relationship with CSF biomarkers and functional parameters. Curr Alzheimer Res. 2010;7:56–66. doi: CAR-40 [pii].
La Joie R, Perrotin A, Barre L, Hommet C, Mezenge F, Ibazizene M. Region-Specific Hierarchy between Atrophy, Hypometabolism, and beta-Amyloid (Abeta) Load in Alzheimer’s Disease Dementia. J Neurosci. 2012;32:16265–73. doi:10.1523/JNEUROSCI.2170-12.2012.
Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.
Choo IH, Lee DY, Oh JS, Lee JS, Lee DS, Song IC. Posterior cingulate cortex atrophy and regional cingulum disruption in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2010;31:772–9. doi:10.1016/j.neurobiolaging.2008.06.015.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–8.
Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004;256:240–6. doi:10.1111/j.1365-2796.2004.01380.x.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939–44.
Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003;19:224–47. doi:10.1002/hbm.10123.
Andreasen N, Hesse C, Davidsson P, Minthon L, Wallin A, Winblad B, et al. Cerebrospinal fluid beta-amyloid (1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch Neurol. 1999;56:673–80.
Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol. 1995;26:231–45. doi:10.1007/BF02815140.
Vanmechelen E, Vanderstichele H, Davidsson P, Van Kerschaver E, Van Der Perre B, Sjogren M, et al. Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett. 2000;285:49–52. doi:S0304-3940 (00) 01036-3 [pii].
Almkvist O, Tallberg IM. Cognitive decline from estimated premorbid status predicts neurodegeneration in Alzheimer’s disease. Neuropsychology. 2009;23:117–24. doi:10.1037/a0014074.
Bergman I, Blomberg M, Almkvist O. The importance of impaired physical health and age in normal cognitive aging. Scand J Psychol. 2007;48:115–25. doi:10.1111/j.1467-9450.2007.00594.x.
Nordberg A, Carter SF, Rinne J, Drzezga A, Brooks DJ, Vandenberghe R, et al. A European multicentre PET study of fibrillar amyloid in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2013;40:104–14. doi:10.1007/s00259-012-2237-2.
Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I. (3) H-deprenyl and (3) H-PIB autoradiography show different laminar distributions of astroglia and fibrillar beta-amyloid in Alzheimer brain. J Neuroinflammation. 2013;10:90. doi:10.1186/1742-2094-10-90.
Small SA, Duff K. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron. 2008;60:534–42. doi:10.1016/j.neuron.2008.11.007.
Whitwell JL, Josephs KA, Murray ME, Kantarci K, Przybelski SA, Weigand SD. MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Neurology. 2008;71:743–9. doi:10.1212/01.wnl.0000324924.91351.7d.
Josephs KA, Whitwell JL, Ahmed Z, Shiung MM, Weigand SD, Knopman DS, et al. Beta-amyloid burden is not associated with rates of brain atrophy. Ann Neurol. 2008;63:204–12. doi:10.1002/ana.21223.
Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 2004;10:719–26. doi:10.1038/nm1058.
Nicoll JA, Weller RO. A new role for astrocytes: beta-amyloid homeostasis and degradation. Trends Mol Med. 2003;9:281–2. doi:10.1016/S1471-4914(03)00109-6.
Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med. 2003;9:453–7.
Nordberg A. Molecular imaging in Alzheimer’s disease: new perspectives on biomarkers for early diagnosis and drug development. Alzheimers Res Ther. 2011;3:34. doi:10.1186/alzrt96.
Nordberg A, Rinne JO, Kadir A, Langstrom B. The use of PET in Alzheimer disease. Nat Rev Neurol. 2010;6:78–87. doi:10.1038/nrneurol.2009.217.
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.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
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)
(GIF 17 kb)
(GIF 18 kb)
(GIF 17 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)
(GIF 17 kb)
(GIF 24 kb)
(GIF 26 kb)
Supplementary Table 1
(PDF 26 kb)
Rights and permissions
About this article
Cite this article
Choo, I.H., Carter, S.F., Schöll, M.L. et al. Astrocytosis measured by 11C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients. Eur J Nucl Med Mol Imaging 41, 2120–2126 (2014). https://doi.org/10.1007/s00259-014-2859-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00259-014-2859-7