The Relationship between White Matter Structure and Clinical Behavior in Different APOE Genotypes: A Preliminary Study in Cognitively Intact Elderly.
Xiao Luo1, Yerfan Jiaerken1, and MinMing Zhang1

1Radiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China, People's Republic of

Synopsis

The purpose of this research was to study the relationship of white matter hyperintensities (WMH) with cognitive performance in healthy elderly with different APOE genotypes. In total, 158 subjects were separated into 3 groups (ε2 carriers, ε4 carriers and ε3 homozygotes). Group differences of regional WMH volume were calculated. Subsequent correlation analysis between regional WMH burden and behavior data was performed. Detrimental effect of APOE ε4 allele on white matter structure was found while no protective effect of APOE ε2 was observed; WMH volume was significantly correlated with processing speed and executive ability, especially in APOE ε4 carriers.

Purpose

Different APOE genotypes have distinct effect on white matter (WM) and cognitive development trajectory. Previous studies reported carrying APOE ε4 allele was related to more severe WMH burden and faster age-related cognitive decline. Conversely, APOE ε2 allele was linked to faster processing of information and superior executive function (1). However, little neuroimage studies have focused on this putative “protective” APOE allele. Meanwhile, limited researches focused on lobar distribution of WMH; actually, varied regions of WMH had totally different clinical implication (2). The purpose of this study was to understand the biologic impact of APOE genotype on WM by measuring regional WMH volume. Besides, we examined whether APOE genotype-related neural endophenotype on WM were associated with clinical behavior performance.

Methods

158 right-handed cognitively intact healthy participants were enrolled, comprised of 30 APOE ε2 carriers, 45 ε4 carriers and 83 ε3 homozygotes, who had undergone MPRAGE scans, T2 FLAIR scans, and neuropsychological assessments. The MPRAGE images and T2FLAIR images were used to create WMH ROIs for each subject, and then each created ROI was divided into 4 smaller ROIs according to lobes. We tested the group differences of WMH volume using ANOVA, and tested the correlations of log-transformed volume of WMH with behavior data.

Results

There were no significant differences regarding age, gender, or education among the groups. Moreover, the gender ratio and history of disease including diabetes, hypertension and smoking were equally distributed among three groups. Besides, no difference in neuropsychological assessments across groups was found. The ε4 carriers had significant increased WMH burden in parietal, occipital and frontal region over other 2 groups; ε2 carriers had a trend of decreased WMH volume in occipital and frontal region relative to the ε3 homozygotes (Fig. 1). Correlation analysis showed, especially in APOE ε4 carriers, WMH volumes of parietal and occipital were significantly related with TMT-A score, and TMT-B score (Details in Fig.2 and Table 1).

Discussion and Conclusion

Our results showed that ε4 carriers had more WMH burden than ε3 homozygotes in frontal and posterior regions. It is known that APOE ε4 allele is associated with aggregation of Aβ protein. Based on these, one of the underlying mechanisms of our observations might be that, the slightly increased amyloid deposition in asymptomatic ε4 carriers affected arterial wall and reduced the vessel lumen, which leads to chronic hypoperfusion in WM (3). Besides, in the periventricular WM (most located in parietal and frontal lobe), the arteriole supplying these areas have traveled long and the anastomoses are scarce. WM in these regions therefore may particularly susceptible to ischemic events resulting from APOE ε4 status (4). Thus, chronic hypoperfusion in these regions were exacerbated by perilous blood supply. Meanwhile, the current study failed to observe a statistically significant “protective” effect of APOE ε2 allele compared to the controls. Given this study was performed in cognitively intact subjects, the low WMH burden in both ε2 carriers and controls may reduce our ability to find any differences.

In addition, our results indicated increased WMH burden in frontal, parietal and occipital regions was significantly related with degeneration of processing speed and executive function. Functionally, the processing of sensory-related information is mainly mediated by dorsal system, including the frontal and posterior parietal area (5). Besides, the parietal/occipital regions served as the “hubs” within the healthy functional brain network, especially the precuneus, had disproportionately numerous connections to other brain regions, was energy demanding and was pivotal for information processing (6). Thus, increased WMH in these regions may disrupt strategic WM tracts and cause a structural “disconnection”, further, disconnect the components of distributed neurocognitive networks. Notably, the correlation was even stronger in ε4 carriers. In contrast, the correlation was weaker or even no longer significant in ε2 carriers and ε3 homozygotes. Such differences in correlation might be explained by the low WMH burden, since mild WMH is generally considered age-related and clinically insignificant.

Conclusively, in this cross-sectional study, we found that the detrimental effect APOE had on WM but failed to spot its “protective” effect; and that WMH may act as a link between APOE ε4 allele and cognitive performance.

Acknowledgements

Xiao Luo and Yerfan Jiaerken contributed equally to this work.

This work is supported by the 12th Five-year Plan for National Science and Technology Supporting Program of China (Grant No.2012BAI10B04) and the National Natural Science Foundation of China (Grant Nos.81371519 and 81301190)

Data used in preparation of this article were obtained from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database (www.adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Besides, data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012).

References

1. Suri S, Heise V, Trachtenberg AJ, Mackay CE. The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE varepsilon2. Neurosci Biobehav Rev 2013; 37:2878-2886.

2. Brickman AM, Schupf N, Manly JJ, et al. APOE epsilon4 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role? Alzheimers Dement 2014; 10:619-629.

3. Attems J, Jellinger K, Thal DR, Van Nostrand W. Review: sporadic cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 2011; 37:75-93.

4. Holland CM, Smith EE, Csapo I, et al. Spatial distribution of white-matter hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging. Stroke 2008; 39:1127-1133.

5. Bonelli RM, Cummings JL. Frontal-subcortical circuitry and behavior. Dialogues Clin Neurosci 2007; 9:141-151.

6. Buckner RL, Sepulcre J, Talukdar T, et al. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci 2009; 29:1860-1873.

Figures

Fig.1. The lobe distribution of WMH volume across groups. The histogram showing ε4 carriers had significant increased WMH burden in parietal, occipital and frontal regions relative to controls; the ε2 carriers had a trend of decreased WMH volume in occipital and frontal region relative to controls.*represents p<0.05.


Fig.2. The scatter plot diagram showing the best-fit line and displaying the correlation relationship between log-transformed WMH volume and clinical behavior score in ε4 carriers, specifically, log-transformed WMH volumes of parietal and occipital were significantly related with TMT-A score (r=0.36; r=0.39, respectively), and TMT-B score (r=0.45; r=0.36, respectively).


Table 1.Correlations of clinical behavioral data and WMH volume in different lobes are shown and significant correlations (p<0.05) were in bold. P, O, F, T represents log transformed WMH volume in parietal, occipital, frontal, and temporal lobe respectively.




Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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