Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not β-amyloid in cognitively normal older individuals - PubMed (original) (raw)

Multicenter Study

Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not β-amyloid in cognitively normal older individuals

Miranka Wirth et al. J Neurosci. 2013.

Abstract

β-Amyloid (Aβ) plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer's disease (AD). This study examined relationships between AD biomarkers of Aβ and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aβ burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [(11)C] Pittsburgh compound B (PIB) positron emission tomography. In the same individuals, we measured hippocampal volume, as well as glucose metabolism and cortical thickness, which were extracted from a template of cortical AD-affected regions. The three functional and structural biomarkers were merged into a highly AD-sensitive multimodality biomarker reflecting neural integrity. In the normal older individuals, there was no association between elevated PIB uptake and either the single-modality or the multimodality neurodegenerative biomarkers. Lower neural integrity within the AD-affected regions and a control area (the visual cortex) was related to lower scores on memory and executive function tests; the same association was not found with PIB retention. The relationship between cognition and the multimodality AD biomarker was stronger in individuals with the highest PIB uptake. The findings indicate that neurodegeneration occurs within AD regions regardless of Aβ deposition and accounts for worse cognition in cognitively normal older people. The impact of neural integrity on cognitive functions is, however, enhanced in the presence of high Aβ burden for brain regions that are most affected in AD.

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Figures

Figure 1.

Figure 1.

Statistical surface maps. A–C, Statistical surface maps (p < 0.00005) for FDG PET (**_A_**), cortical thickness (cThick) (**_B_**), and the FDG/cThick convergence (**_C_**) as derived from the group contrast (ADNI NC > ADNI AD) in the derivation sample. For each surface map, significant clusters are color-coded. Yellow coloring illustrates cortical regions with the most significant AD-related hypometabolism and thinning. The red boundary in C indicates that the cluster size (cs) exceeded the minimum threshold of 300 mm2.

Figure 2.

Figure 2.

Validation of the AD neurodegenerative biomarkers. Distribution of the neurodegenerative biomarkers in the derivation (ADNI NC [blue], ADNI AD [orange]) and validation (BAC NC [black], UCSF AD [red]) samples. A, The multimodality biomarker was reduced for AD patients compared with normal controls (NC) across samples. The gray line denotes the discriminant cutoff score (values ≤0 indicate AD classification). B–D, The single-modality biomarkers, i.e., cortical thickness (B), FDG PET (C), intracranial volume-adjusted hippocampal volume (HVicv) (D), showed prominent reductions for AD patients across samples. Error bar plots display group-means and SD for each biomarker; the gray circles indicate individual data points.

Figure 3.

Figure 3.

Relationships between the AD neurodegenerative biomarkers and PIB uptake. Distribution of the neurodegenerative biomarkers in PIB negative (BAC NC PIB− [white]) and PIB positive (BAC NC PIB+ [solid black]) individuals. A, The multimodality biomarker values were comparable for PIB+ and PIB− individuals. The gray line denotes the discriminant cutoff score (values ≤0 indicate AD classification). B–D, There were no significant differences in the single-modality biomarkers, i.e., cortical Thickness (B), FDG PET (C) and intracranial volume-adjusted hippocampal volume (HVicv) (D), between PIB+ and PIB− subjects. Error bar plots display group-means and SD for each biomarker; the gray circles indicate individual data points.

Figure 4.

Figure 4.

Relationships between the AD neurodegenerative biomarker and cognition. A, B, Relationships between the multimodality biomarker and memory performance (A) as well as executive functions (B) in the BAC NC sample. The scatter plots show that lower values of the multimodality biomarker were related to lower memory and executive function. Unadjusted data are depicted; linear trends (dark solid line), 95% confidence intervals (light solid line), and individual data points (gray circles) are specified.

Figure 5.

Figure 5.

Interaction between the neurodegenerative biomarkers and PIB uptake. A, B, Relationships between the multimodality biomarker and memory performance (A) as well executive functions (B) for the PIB uptake groups of the BAC NC sample. The scatter plots show that for the AD regions (top) the association between the neurodegenerative biomarker and cognitive performance was significantly stronger for individuals with high PIB uptake (high PIB+ [solid black trend line]) compared with PIB negative (PIB−) subjects. For the control region, no significant interactions were observed (see text). Unadjusted data are depicted; linear trends (lines) and individual data points (circles) are specified.

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