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BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF

Published online by Cambridge University Press:  19 July 2017

Yen Ying Lim ,
Stephanie Rainey-Smith ,
Yoon Lim ,
Simon M. Laws ,
Veer Gupta ,
Tenielle Porter ,
Pierrick Bourgeat ,
David Ames ,
Christopher Fowler  and
Olivier Salvado
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Yen Ying Lim*
Affiliation:
The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia
Stephanie Rainey-Smith
Affiliation:
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia
Yoon Lim
Affiliation:
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Simon M. Laws
Affiliation:
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia, Australia Co-operative Research Centre for Mental Health, Carlton South, Victoria, Australia
Veer Gupta
Affiliation:
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia
Tenielle Porter
Affiliation:
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia, Australia Co-operative Research Centre for Mental Health, Carlton South, Victoria, Australia
Pierrick Bourgeat
Affiliation:
Commonwealth Scientific Industrial Research Organization (CSIRO) Preventative Health National Research Flagship, Australian e-Health Research Centre-BiaMedIA, Brisbane, Queensland, Australia
David Ames
Affiliation:
Academic Unit for Psychiatry of Old Age, St. Vincent's Health, The University of Melbourne, Kew, Victoria, Australia National Ageing Research Institute, Parkville, Victoria, Australia
Christopher Fowler
Affiliation:
The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia
Olivier Salvado
Affiliation:
Commonwealth Scientific Industrial Research Organization (CSIRO) Preventative Health National Research Flagship, Australian e-Health Research Centre-BiaMedIA, Brisbane, Queensland, Australia
Victor L. Villemagne
Affiliation:
The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria, Australia Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Christopher C. Rowe
Affiliation:
Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, Victoria, Australia Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Colin L. Masters
Affiliation:
The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia
Xin Fu Zhou
Affiliation:
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Ralph N. Martins
Affiliation:
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia
Paul Maruff
Affiliation:
The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia Cogstate Ltd., Melbourne, Victoria, Australia
*
Correspondence should be addressed to: Yen Ying Lim, The Florey Institute of Neuroscience and Mental Health, 155 Oak Street, Parkville, VIC 3052, Australia. Phone: +61 3 9389 2909; Fax: +61 3 9387 5061. Email: [email protected].
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Abstract

Background:

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36–54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months.

Methods:

Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ– or Aβ+.

Results:

At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ– Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF.

Conclusion:

While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.

Keywords

brain-derived neurotrophic factorAlzheimer's diseasememoryhippocampal volume
Type
Research Article
Information
International Psychogeriatrics , Volume 29 , Issue 11 , November 2017 , pp. 1825 - 1834
Copyright
Copyright © International Psychogeriatric Association 2017 

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Footnotes

*

Co-first authors on this manuscript

References

Angelucci, F. et al. (2010). Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) patients are characterized by increased BDNF serum levels. Current Alzheimer Research, 7, 15–20.Google Scholar
Caccamo, A., Maldonado, M. A., Bokov, A. F., Majumder, S. and Oddo, S. (2010). CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 107, 22687–22692.Google Scholar
Clark, C. M. et al. (2011). Use of florbetapir-PET for imaging beta-amyloid pathology. Journal of the American Medical Association, 305, 275–283.Google Scholar
Egan, M. F. et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269.Google Scholar
Elliott, E., Atlas, R., Lange, A. and Ginzburg, I. (2005). Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3 kinase signaling mechanism. European Journal of Neuroscience, 22, 1081–1089.CrossRefGoogle Scholar
Ellis, K. A. et al. (2009). The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease. International Psychogeriatrics, 21, 672–687.Google Scholar
Fahnestock, M. (2011). Brain-derived neurotrophic factor: the link between amyloid-b and memory loss. Future Neurology, 6, 627–639.CrossRefGoogle Scholar
Ferrer, I. et al. (1999). BDNF and full-length and truncated TrkB expression in Alzheimer disease: implications in therapeutic strategies. Journal of Neuropathology and Experimental Neurology, 58, 729–739.CrossRefGoogle ScholarPubMed
Forlenza, O. V. et al. (2010). Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World Journal of Biological Psychiatry, 11, 774–780.CrossRefGoogle ScholarPubMed
Garzon, D. J. and Fahnestock, M. (2007). Oligomeric amyloid decreases basal levels of brain-derived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells. The Journal of Neuroscience, 27, 2628–2635.Google Scholar
Hariri, A. R. et al. (2003). Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. The Journal of Neuroscience, 23, 6690–6694.Google Scholar
Kim, A. et al. (2015). Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory. Cognitive, Affective & Behavioral Neuroscience, 15, 625–643.Google Scholar
Lang, U. E., Hellweg, R., Sander, T. and Gallinat, J. (2009). The met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations. Molecular Psychiatry, 14, 120–122.CrossRefGoogle ScholarPubMed
Laske, C. et al. (2011). Higher BDNF serum levels predict slower cognitive decline in Alzheimer's disease patients. International Journal of Neuropsychopharmacology, 14, 399–404.Google Scholar
Laske, C. et al. (2007). BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls. Journal of Psychiatric Research, 41, 387–394.CrossRefGoogle ScholarPubMed
Lee, S. T. et al. (2012). miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. Annals of Neurology, 72, 269–277.Google Scholar
Lim, Y. Y. et al. (2014a). Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer's disease. Brain, 137, 221–231.Google Scholar
Lim, Y. Y. et al. (2013). BDNF Val66Met, Aβ amyloid and cognitive decline in preclinical Alzheimer's disease. Neurobiology of Aging, 34, 2457–2464.CrossRefGoogle ScholarPubMed
Lim, Y. Y. et al. (2014b). BDNF Val66Met moderates Aβ-related memory decline and hippocampal atrophy in prodromal Alzheimer's disease: a preliminary study. PLoS One, 9, e86498.Google Scholar
Lim, Y. Y. et al. (2015a). APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer's disease. Molecular Psychiatry, 20, 1322–1328.CrossRefGoogle ScholarPubMed
Lim, Y. Y. et al. (2016). BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease. Brain, 139, 2766–2777.CrossRefGoogle ScholarPubMed
Lim, Y., Zhong, J. H. and Zhou, X. F. (2015b). Development of mature BDNF-specific sandwich ELISA. Journal of Neurochemistry, 134, 75–85.Google Scholar
Lu, B., Nagappan, G., Guan, X., Nathan, P. J. and Wren, P. (2013). BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nature Reviews, Neuroscience, 14, 401–416.Google Scholar
Masters, C. L. and Selkoe, D. J. (2012). Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease. In Selkoe, D. J., Mandelkow, E. and Holtzman, D. M. (eds.), The Biology of Alzheimer Disease, (pp. 181–204). New York: Cold Spring Harbor Laboratory Press.Google Scholar
Morris, J. C. (1983). The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology, 43, 2412–2414.CrossRefGoogle Scholar
O'Bryant, S. E. et al. (2009). Brain-derived neurotrophic factor levels in Alzheimer's disease. Journal of Alzheimer's Disease, 17, 337–341.Google Scholar
Peng, S., Wuu, J., Mufson, E. J. and Fahnestock, M. (2005). Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the preclinical stages of Alzheimer's disease. Journal of Neurochemistry, 93, 1412–1421.Google Scholar
Rosa, E. and Fahnestock, M. (2015). CREB expression mediates amyloid β-induced basal BDNF downregulation. Neurobiology of Aging, 36, 2406–2413.CrossRefGoogle ScholarPubMed
Rowe, C. C. et al. (2010). Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiology of Aging, 31, 1275–1283.Google Scholar
Shimada, H. et al. (2014). A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Frontiers in Aging Neuroscience, 15, 1–9.Google Scholar
Vandenberghe, R. et al. (2010). 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Annals of Neurology, 68, 319–329.Google Scholar
Villemagne, V. L. et al. (2011). Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Annals of Neurology 69, 181–192.Google Scholar
Wong, D. F. et al. (2010). In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). Journal of Nuclear Medicine, 51, 913–920.Google Scholar
Yu, H et al. (2008). Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han. Journal of Clinical Psychiatry, 69, 1104–1111.CrossRefGoogle ScholarPubMed