Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers

Figures

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  Fig. 1. Gray matter reductions in preSxC9. (A) Group difference maps derived using VBM illustrate reduced gray matter in 15 preSxC9 expansion carriers compared with 67 healthy controls (HC2) involving bilateral posterior midcingulate cortex, left medial pulvinar nucleus of the thalamus, and regions in bilateral dorsolateral prefrontal cortex at pFWE < 0.05 (dark blue). More extensive gray matter reductions in bilateral medial frontal cortex, dorsolateral prefrontal cortex, insula, precuneus and medial thalamus emerge at p < 0.001 uncorrected (cyan). Color bars represent t-scores, and statistical maps are superimposed on the Montreal Neurological Institute template brain. The left side of the axial and coronal images corresponds to the left side of the brain. (B) Mean gray matter intensity versus age within the pFWE < 0.05 map in (A), for 15 preSxC9 (blue dots), C9– (black dots), and HC (black circles) plotted for visualization purposes only. In general, preSxC9 showed lower gray matter intensities within the pFWE < 0.05 map in (A) compared with controls over three decades. Age axis labels are omitted to preserve subject anonymity. C9 + = presymptomatic C9ORF72 expansion carriers; C9– =…

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  Fig. 2. Reduced white matter integrity in preSxC9. (A) Group difference FA maps show reduced fractional anisotropy in 12 preSxC9 compared with 29 healthy controls (HC3) including left greater than right cingulum bundle and corpus callosum and bilateral internal capsule at p < 0.05 corrected (blue-green). Color bars represent p values, and statistical maps are superimposed on the FMRIB58FA template. The left side of the axial and coronal images corresponds to the left side of the brain. (B) Mean FA versus age within the map in (A), for 12 preSxC9 (blue dots), C9– (black dots), and HC (black circles) plotted for visualization purposes only. PreSxC9 showed lower FA within the map in (A) compared with controls over three decades. Age axis labels are omitted to preserve subject anonymity. C9 + = presymptomatic C9ORF72 expansion carriers; C9– = non-carrier family members; HC = non-family healthy controls. C9– and HC were combined to comprise HC3.

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  Fig. 3. ICN reductions in preSxC9. Group difference maps show reduced intrinsic connectivity in 13 preSxC9 compared with 30 healthy controls (HC3) for all four networks studied: (A) salience network; (B) SMN; (C) DMN; and (D) medial pulvinar. Note the topographic similarity of connectivity reductions in the salience network (A) and medial pulvinar network (D). Analyses were thresholded using joint probability distribution thresholding with a joint height and extent threshold of p < 0.05 corrected at the whole-brain level. Color bars represent t-scores, and statistical maps are on the Montreal Neurological Institute template brain. The left side of the axial and coronal images corresponds to the left side of the brain. Mean ICN parameter estimate versus age within the maps at left are plotted for 13 preSxC9 (blue dots), C9– (black dots), and HC (black circles). All four plots suggest ICN reductions throughout the age span studied. Age axis labels are omitted to preserve subject anonymity. C9 + = presymptomatic C9ORF72 expansion carriers; C9– = non-carrier family members (black dots); HC = non-family healthy controls. C9– and HC were combined to comprise HC3.

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  Fig. 4. Salience and medial pulvinar connectivity disruptions predominate in preSxC9. In (A), the pie chart shows the percentage of preSxC9 participants in whom the salience network (blue), SMN (purple), DMN (green), or medial pulvinar connectivity (red) was the ICN with the lowest connectivity w-score among the four ICNs. (B) w-scores of mean connectivity reveal that 13 preSxC9 show heterogeneous ICN reduction profiles, with salience and medial pulvinar networks showing most disruption across the age span. Subjects are ordered by ascending age. (C) Fit-lines of the w-scores in B show that salience and medial pulvinar connectivity are the lowest throughout the presymptomatic phase.

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  Fig. 5. Multimodal imaging composite scores separate preSxC9 from controls and show structural and functional connectivity disruption as early as the third decade. (A) The plot shows a w-score composite (the average of gray matter intensity, fractional anisotropy and lowest ICN w-scores for each subject) plotted versus age. The C9 + fit line appears horizontal, thus suggesting a consistently reduced w-score composite across the entire age range. (B) Individual C9 + subject w-scores from VBM, DTI, and ICN analyses for the most reduced ICN for each subject in order of ascending age. (C) Effect size (Cohen's d) for detecting differences between C9 + and controls for VBM, DTI, and most reduced (weakest) ICN. C9 + = presymptomatic C9ORF72 expansion carriers (black dots); C9– = non-carrier family members (black circles); HC = healthy controls included in all three imaging modalities (indicated by “x”). Axis labels for age were omitted to preserve anonymity.

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  Fig. 6. Psychiatric histories in preSxC9 and C9ORF72 family members negative for the expansion. No statistically significant differences emerged in preSxC9 (C9 +, black bars, N = 15) versus their expansion-negative family members (C9 −, gray bars, N = 24) for psychiatric symptoms (Psych Sx), psychiatric or psychological treatment (Psych Tx), psychiatric medications (Psych Meds), psychiatric hospitalizations (Psych Hosp), prolonged substance use or abuse (Subs Use), or childhood neurological developmental disorders (Dev Dis).