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Polymorphism of brain derived neurotrophic factor influences ? amyloid load in cognitively intact apolipoprotein E ?4 carriers.

ABSTRACT: Aside from apolipoprotein E (APOE), genetic risk factors for ? amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects ? amyloid burden and the relationship between ? amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of (18)F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (?4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ?4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ?4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ?4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of ? amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against ? amyloid-related effects on cognition.

SUBMITTER: Adamczuk K

PROVIDER: S-EPMC3777754 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers.

Adamczuk Katarzyna K De Weer An-Sofie AS Nelissen Natalie N Chen Kewei K Sleegers Kristel K Bettens Karolien K Van Broeckhoven Christine C Vandenbulcke Mathieu M Thiyyagura Pradeep P Dupont Patrick P Van Laere Koen K Reiman Eric M EM Vandenberghe Rik R

NeuroImage. Clinical 20130411

Aside from apolipoprotein E (APOE), genetic risk factors for β amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects β amyloid burden and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was ...[more]

PMID: 24179803

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Project description:Observations in animal models suggest that amyloid can cause network hypersynchrony in the early preclinical phase of Alzheimer's disease (AD). The aim of this study was (a) to obtain evidence of paroxysmal hypersynchrony in cognitively intact subjects (CN) with increased brain amyloid load from task-free fMRI exams using a dynamic analysis approach, (b) to investigate if and how hypersynchrony interferes with memory performance, and (c) to describe its relationship with gray and white matter connectivity. Florbetapir-F18 PET and task-free 3T functional and structural MRI were acquired in 47 CN (age = 70.6 ± 6.6), 17 were amyloid pos (florbetapir SUVR >1.11). A parcellation scheme encompassing 382 regions of interest was used to extract regional gray matter volumes, FA-weighted fiber tracts and regional BOLD signals. Graph analysis was used to characterize the gray matter atrophy profile and the white matter connectivity of each subject. The fMRI data was processed using a combination of sliding windows, graph and hierarchical cluster analysis. Each activity cluster was characterized by identifying strength dispersion (difference between pos and neg strength) their maximal and minimal pos and neg strength rois and by investigating their distribution and association with memory performance and gray and white matter connectivity using spearman rank correlations (FDR p < 0.05). The cluster analysis identified eight different activity clusters. Cluster 8 was characterized by the largest strength dispersion indicating hypersynchrony. Its duration/subject was positively correlated with amyloid load (r = 0.42, p = 0.03) and negatively with memory performance (CVLT delayed recall r = -0.39 p = 0.04). The assessment of the regional strength distribution indicated a functional disconnection between mesial temporal structures and the rest of the brain. White matter connectivity was increased in left lateral and mesial temporal lobe and was positively correlated with strength dispersion in the cross-modality analysis suggesting that it enables widespread hypersynchrony. In contrast, precuneus, gray matter connectivity was decreased in the right fusiform gyrus and negatively correlated with high degrees of strength dispersion suggesting that progressing gray matter atrophy could prevent the generation of paroxysmal hypersynchrony in later stages of the disease.

Dataset Information

Polymorphism of brain derived neurotrophic factor influences ? amyloid load in cognitively intact apolipoprotein E ?4 carriers.

Publications

Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers.

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