Effects of gene mutation and disease progression on representative neural circuits in familial Alzheimer's disease

Meina Quan, Tan Zhao, Yi Tang, Ping Luo, Wei Wang, Qi Qin, Tingting Li, Qigeng Wang, Jiliang Fang, Jianping Jia, Meina Quan, Tan Zhao, Yi Tang, Ping Luo, Wei Wang, Qi Qin, Tingting Li, Qigeng Wang, Jiliang Fang, Jianping Jia

Abstract

Background: Although structural and functional changes of the striatum and hippocampus are present in familial Alzheimer's disease, little is known about the effects of specific gene mutation or disease progression on their related neural circuits. This study was to evaluate the effects of known pathogenic gene mutation and disease progression on the striatum- and hippocampus-related neural circuits, including frontostriatal and hippocampus-posterior cingulate cortex (PCC) pathways.

Methods: A total of 102 healthy mutation non-carriers, 40 presymptomatic mutation carriers (PMC), and 30 symptomatic mutation carriers (SMC) of amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 gene, with T1 structural MRI, diffusion tensor imaging, and resting-state functional MRI were included. Representative neural circuits and their key nodes were obtained, including bilateral caudate-rostral middle frontal gyrus (rMFG), putamen-rMFG, and hippocampus-PCC. Volumes, diffusion indices, and functional connectivity of circuits were compared between groups and correlated with neuropsychological and clinical measures.

Results: In PMC, APP gene mutation carriers showed impaired diffusion indices of caudate-rMFG and putamen-rMFG circuits; PS1 gene mutation carriers showed increased fiber numbers of putamen-rMFG circuit. SMC showed increased diffusivity of the left hippocampus-PCC circuit and volume reduction of all regions as compared with PMC. Imaging measures especially axial diffusivity of the representative circuits were correlated with neuropsychological measures.

Conclusions: APP and PS1 gene mutations affect frontostriatal circuits in a different manner in familial Alzheimer's disease; disease progression primarily affects the structure of hippocampus-PCC circuit. The structural connectivity of both frontostriatal and hippocampus-PCC circuits is associated with general cognitive function. Such findings may provide further information about the imaging biomarkers for early identification and prognosis of familial Alzheimer's disease, and pave the way for early diagnosis, gene- or circuit-targeted treatment, and even prevention.

Keywords: Diffusion tensor imaging; Familial Alzheimer’s disease; Gene mutation; Neural circuits; Resting-state functional MRI.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The ROIs of a representative subject in structural space. The subcortical ROIs (a) include the bilateral caudate (yellow), putamen (green), and hippocampus (blue); the cortical ROIs (b) include rMFG (red) and PCC (brown)
Fig. 2
Fig. 2
Overall group comparison of the ROI volume. a) left caudate, b) right caudate, c) left putamen, d) right putamen, e) left hippocampus, f) right hippocampus, g) left rMFG, h) right rMFG, i) left PCC, j) right PCC. Relative volume of each subject is calculated as the percentage of absolute volume in intracranial volume. The bars indicate mean (SD). rMFG: rostrol middle frontal gyrus; PCC: posterior cingulate cortex; Hippo: hippocampus; L: left; R: right. #0.0167 < P < 0.05, *0.01 < P < 0.0167, **0.001 < P < 0.01, ***P < 0.001
Fig. 3
Fig. 3
The ROIs and tracts of a representative subject in diffusion space. The tracts (pink) include the bilateral caudate-rMFG (a), putamen-rMFG (b), and hippocampus-PCC (c). The ROIs are in the same color with those in Fig. 1
Fig. 4
Fig. 4
Overall group comparison of the structural and functional connectivity of neural circuits. a) fiber numbers of left caudate-rMFG tract, b) MD of right caudate-rMFG tract, c) AxD of right caudate-rMFG tract, d) RD of right caudate-rMFG tract, e) AxD of left hippo-PCC tract, f) FC of left caudate-rMFG tract. MD: mean diffusivity; AxD: axial diffusivity; RD: radial diffusivity; FC: functional connectivity. The bars indicate mean (SD). #0.0167 < P < 0.05, *0.01 < P < 0.0167, **0.001 < P < 0.01
Fig. 5
Fig. 5
Effects of gene mutation on the imaging measures of neural circuits. a) relative volume of right putamen, b) fiber numbers of left putamen-rMFG tract, c) fiber numbers of left caudate-rMFG tract, d) FA of left caudate-rMFG tract, e) RD of left caudate-rMFG tract, f) MD of right caudate-rMFG tract, g) RD of right caudate-rMFG tract, h) FC of left caudate-rMFG tract. PS1 and APP mutation subjects without symptoms were compared with the control group, respectively. PS2 mutation subjects were listed for reference though not compared with the control group due to the small sample size. The bars indicate mean (SD). # 0.025 < P < 0.05, * 0.01 < P < 0.025
Fig. 6
Fig. 6
Comparison of ROI volume among different stages of mutation carriers. a) left caudate, b) right caudate, c) left putamen, d) right putamen, e) left hippocampus, f) right hippocampus, g) left rMFG, h) right rMFG, i) left PCC, j) right PCC. Pre-MCI represents presymptomatic stage (original PMC group). The bars indicate mean (SD). # 0.0167 < P < 0.05, * 0.01 < P < 0.0167, ** 0.001 < P < 0.01, ***P < 0.001
Fig. 7
Fig. 7
Group comparisons done

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