Diffusion Tensor MRI Structural Connectivity and PET Amyloid Burden in Preclinical Autosomal Dominant Alzheimer Disease: The DIAN Cohort

Abstract

Background Pathologic evidence of Alzheimer disease (AD) is detectable years before onset of clinical symptoms. Imaging-based identification of structural changes of the brain in people at genetic risk for early-onset AD may provide insights into how genes influence the pathologic cascade that leads to dementia. Purpose To assess structural connectivity differences in cortical networks between cognitively normal autosomal dominant Alzheimer disease (ADAD) mutation carriers versus noncarriers and to determine the cross-sectional relationship of structural connectivity and cortical amyloid burden with estimated years to symptom onset (EYO) of dementia in carriers. Materials and Methods In this exploratory analysis of a prospective trial, all participants enrolled in the Dominantly Inherited Alzheimer Network between January 2009 and July 2014 who had normal cognition at baseline, T1-weighted MRI scans, and diffusion tensor imaging (DTI) were analyzed. Amyloid PET imaging using Pittsburgh compound B was also analyzed for mutation carriers. Areas of the cerebral cortex were parcellated into three cortical networks: the default mode network, frontoparietal control network, and ventral attention network. The structural connectivity of the three networks was calculated from DTI. General linear models were used to examine differences in structural connectivity between mutation carriers and noncarriers and the relationship between structural connectivity, amyloid burden, and EYO in mutation carriers. Correlation network analysis was performed to identify clusters of related clinical and imaging markers. Results There were 30 mutation carriers (mean age ± standard deviation, 34 years ± 10; 17 women) and 38 noncarriers (mean age, 37 years ± 10; 20 women). There was lower structural connectivity in the frontoparietal control network in mutation carriers compared with noncarriers (estimated effect of mutation-positive status, -0.0266; P = .04). Among mutation carriers, there was a correlation between EYO and white matter structural connectivity in the frontoparietal control network (estimated effect of EYO, -0.0015, P = .01). There was no significant relationship between cortical global amyloid burden and EYO among mutation carriers (P > .05). Conclusion White matter structural connectivity was lower in autosomal dominant Alzheimer disease mutation carriers compared with noncarriers and correlated with estimated years to symptom onset. Clinical trial registration no. NCT00869817 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by McEvoy in this issue.

Conflict of interest statement

Disclosures of Conflicts of Interest: J.W.P. disclosed no relevant relationships. P.M.D. disclosed compensation received for board membership at AHEL; received advisor fees from Neuroglee, Transposon Therapeutics, VitaKey, and Verily Life Sciences; received grants from Lilly, Avid Medical, Avanir, and Bausch; has patents related to Alzheimer disease diagnosis and therapy; has stock or stock options in uMETHOD, Evidation, Transposon Therapeutics, and Advera Health. D.G. disclosed no relevant relationships. T.B. disclosed support from Biogen for travel to meetings for the study; received consulting fees from Biogen; has performed unpaid consulting for Eisai, Siemens, and ADMdx; received payment for lectures and the development of educational presentations from Biogen. J.R.P. disclosed no relevant relationships.

Figures

Figure 1:

Cortical areas involved with each of the three distributed cortical association networks analyzed are displayed on an inflated brain surface, viewed from the lateral aspect (top row) and the medial aspect (bottom row) of the left hemisphere; the right hemisphere (not shown) is nearly a mirror image of the left hemisphere. The regions are based on a standard functional parcellation of the human brain from a resting-state functional MRI study of 1000 healthy individuals. The three specific networks of interest are the ventral attention network (purple), default mode network (red), and frontoparietal control network (orange). Cortical regions in the ventral attention network include portions of the middle frontal gyrus, inferior frontal gyrus (pars triangularis and pars opercularis), insula, supramarginal gyrus, posterior superior temporal sulcus, superior frontal gyrus, anterior and posterior cingulate, and precuneus. Cortical regions in the default mode network include portions of the medial prefrontal cortex; precuneus; posterior cingulate; parahippocampal gyrus; superior, middle, and inferior temporal gyri; and inferior parietal gyrus. Cortical regions in the frontoparietal control network include portions of the superior and middle frontal gyri, inferior temporal gyrus, supramarginal gyrus, anterior and posterior cingulate, and precuneus. Note that some of the gyral-based parcellated areas are components of more than one network defined by the functional parcellation. Source.–Reference .

Figure 2:

Example structural connectivity of the three analyzed distributed cortical networks from one participant in the DIAN cohort, viewed laterally from the left (top row) and anteriorly (bottom row). The networks are from a standard functional parcellation of the human cortex shown in Figure 1. Streamline colors indicate directionality of water diffusion at diffusion tensor imaging: green = anteroposterior, red = left-right, blue = superoinferior.

Figure 3:

Scatterplots show global efficiency in the frontoparietal control network versus estimated years to symptom onset (EYO) (top) and Pittsburgh compound B amyloid PET standardized uptake value ratio (SUVr) (bottom) in cognitively normal mutation-positive participants. The EYO axis in the top figure only has the 0 value plotted to protect against the unintended unblinding of mutation status for an individual at the extremes of the data, per Dominantly Inherited Alzheimer Network policy. The data in these plots, including R2 and P values, are not adjusted for multiple comparisons or for covariates that are in the statistical model defined in Equation (E2) (online).

Figure 4:

Correlation networks for noncarriers (top) and mutation carriers (bottom). Baseline clinical and biologic marker descriptors are denoted with circles. Circles are shaded orange for amyloid PET standardized uptake value ratio, yellow for structural connectivity measures, green for cognitive measures, purple for age, blue for education (Educ), and red for estimated years to symptom onset (EYO). The cognitive measures include word recall–immediate (Word Imm), word recall–delayed (Word Del), logical memory–immediate (Logic Mem), and logical memory–delayed (Mem Units). DTI = diffusion tensor imaging, Front Par = frontoparietal control network, Vent Att = ventral attention network.